Burl R. Don MD
Morris Schambelan MD
Joan C. Lo MD
Arterial hypertension is a prominent component of a number of endocrine disorders, most prominently those involving the adrenal glands (pheochromocytoma, primary aldosteronism) and the pituitary (ACTH-producing tumors). Although the kidney is not an endocrine organ per se, its role as both the origin of and target tissue for the hormones that comprise the renin-angiotensin-aldosterone system makes hypertensive disorders of renal origin an appropriate subject for a chapter on endocrine hypertension. Hypertension may also be a prominent feature of other endocrine disorders such as acromegaly, thyrotoxicosis, hypothyroidism, and hyperparathyroidism, but these topics are considered elsewhere in this volume and will not be discussed in any detail here.
HYPERTENSION OF ADRENAL ORIGIN
SYNTHESIS, METABOLISM, & ACTION OF MINERALOCORTICOID HORMONES
The biosynthetic pathways of the mineralocorticoid hormones are shown in Figure 10-1. The major adrenal secretory products with mineralocorticoid activity are aldosterone and 11-deoxycorticosterone (DOC). Cortisol also has high intrinsic mineralocorticoid activity, but, as discussed in a subsequent section, its actions in the kidney are blunted by local degradation. Aldosterone is produced exclusively in the zona glomerulosa and is primarily controlled by the renin-angiotensin system. Other regulators include Na+ and K+ levels, ACTH, and dopamine. With the exception of 18-hydroxycorticosterone, the precursors of aldosterone that originate in the zona glomerulosa are normally present in very low concentrations in the peripheral blood. In the zona fasciculata, the two major biosynthetic pathways are under the control of ACTH. The major product formed by the 17-hydroxy pathway is cortisol. The principal steroid product of the 17-deoxy pathway with significant mineralocorticoid activity is DOC. Corticosterone and 18-hydroxydeoxycorticosterone are also produced in substantial amounts, but these steroids have relatively little mineralocorticoid activity in humans.
Aldosterone binds weakly to corticosteroid-binding globulin (CBG)—in contrast to steroids made in the zona fasciculata—and circulates mostly bound to albumin. Free aldosterone comprises 30–50% of its total plasma concentration, whereas the free fractions of the steroid products of the zona fasciculata comprise 5–10% of their total concentration. Consequently, aldosterone has a relatively short half-life, on the order of 15–20 minutes. Aldosterone is rapidly inactivated in the liver, with formation of tetrahydroaldosterone.
Another metabolite, aldosterone-18-glucuronide, is formed by the kidney and usually represents 5–10% of the secreted aldosterone. A small amount of free aldosterone appears in the urine and can be easily quantitated. Aldosterone secretion rates vary from 50 to 250 ľg/d on Na+intakes in the range of 100–150 mmol/d.
Figure 10-1. Biosynthetic pathways of the mineralocorticoids. (See also Figures 2-6, 9-4, 9-5, and 14-13. And see Table 9-1 for current gene symbols for steroidogenic enzymes.)
DOC is secreted at approximately the same rate as aldosterone. However, like cortisol, DOC is almost totally bound to CBG, with less than 5% appearing in the free form. It is metabolized in the liver to tetrahydrodeoxycorticosterone, conjugated with glucuronic acid, and excreted in the urine. There is virtually no free DOC detectable in the urine.
Mineralocorticoid activity reflects the availability of free hormone and the affinity of the hormone for the receptor. Aldosterone and DOC have approximately equal and high affinities for the mineralocorticoid receptor and circulate at roughly similar concentrations, but aldosterone is quantitatively the most important because much more of it is free. Cortisol has an affinity for the receptor similar to that of aldosterone and its free levels in the circulation are about 100-fold higher than those of aldosterone. Because of this, cortisol is the major steroid that occupies the mineralocorticoid receptors in many tissues such as the pituitary and heart; however, at normal circulating levels, cortisol does not contribute much to mineralocorticoid action in typical target tissues (kidney, colon, salivary glands) because of local conversion (via 11β-hydroxysteroid dehydrogenase) to cortisone. Cortisol can lead to mineralocorticoid hypertension when this conversion is blunted by deficiency or inhibition of this enzyme (discussed subsequently).
Aldosterone and other mineralocorticoids influence certain ion-transporting epithelia with high Na+-K+ ATPase levels. The principal effects of the mineralocorticoids are on maintenance of normal Na+ and K+ concentrations and extracellular fluid volume. Mineralocorticoids cross the cell membrane and combine with a mineralocorticoid receptor in the cytosol (see Chapter 3 and Figure 3-12). The active steroid-receptor complex moves into the nucleus of the target cell, where it alters the rate of transcription of mineralocorticoid-responsive genes with subsequent changes in the levels of specific mRNAs and their protein products. The aldosterone-induced proteins include factors that regulate the luminal Na+ channel, facilitating movement of Na+ into cells, and components of the Na+-K+ ATPase pump. The principal early effect of aldosterone (beginning in less than 1 hour) is on the Na+ channel. Without altering overall channel abundance, aldosterone increases the apical membrane targeting, or the probability of open channels, already synthesized, in
the collecting tubule and part of the distal convoluted tubule. Recently, a key mediator of the early response was identified as an aldosterone-regulated kinase (serum glucocorticoid-regulated kinase; SGK) that increases Na+ channel activity. The later effects (occurring 6–24 hours after hormone administration) of aldosterone include activation of Na+-K+ ATPase and alterations in cell morphology and energy metabolism. Some or all of these may be due to the altered intracellular Na+ concentrations that result from the primary effect on the Na+channel. In addition to directly enhancing Na+ absorption, the major effect of these aldosterone-induced changes in ion transport is to increase the difference in electrical potential across the renal tubule. The increased luminal negativity augments tubular secretion of K+ by the principal cell and H+ by the intercalated cell (Figure 10-2). Tubular Na+, via the Na+ pump, enters the extracellular fluid and helps maintain its normal composition and volume. All of these events occur in other secretory systems as well and can be measured in saliva, sweat, and feces.
PATHOGENESIS OF MINERALOCORTICOID HYPERTENSION
Mineralocorticoid hormones produce hypertension by several mechanisms (Figure 10-3). The initiating events are the physiologic consequences of mineralocorticoid-induced expansion of plasma and extracellular fluid volume. Insights into these early mechanisms come from studies in normal subjects given high doses of mineralocorticoids and from sequential observations made following discontinuation of spironolactone therapy in patients with aldosterone-secreting adenomas. Initially, Na+ and fluid retention occur, with an increase in body weight, extracellular fluid volume, and cardiac output. After gaining 1–2 L of additional extracellular fluid, the phenomenon of Na+ “escape” follows, so that a new steady state is achieved. Renal K+ wasting persists and arterial blood pressure continues to increase, however. Typically, the chronic stage of mineralocorticoid excess is characterized by an increase in total peripheral vascular resistance and normalization of stroke volume and cardiac output. The increase in peripheral vascular resistance is related in part to increased sensitivity to catecholamines even without a distinct increment in plasma epinephrine or norepinephrine levels. An additional mechanism may be a direct central action of aldosterone: Intracerebroventricular infusion of aldosterone to rats produced hypertension that could not be reversed or prevented by infusion, at the same site, of a competitive aldosterone antagonist.
Figure 10-2. Mineralocorticoid action. On the left, rates of tubular sodium delivery together with increased mineralocorticoid action lead to K+ and H+ secretion and Na+ movement into extracellular fluid. On the right, similar amounts of mineralocorticoid are ineffective when tubular sodium is reduced (eg, by dietary sodium restriction).
Primary mineralocorticoid excess is manifested by hypertension, hypokalemia, and suppression of the renin-angiotensin system. Primary aldosteronism is the prototypic disorder and will be described in the greatest detail. Clinically similar syndromes can result from increased adrenal production of other steroids with mineralocorticoid activity (eg, DOC), failure to inactivate cortisol (eg, syndrome of apparent mineralocorticoid excess), or as a consequence of mineralocorticoid-independent augmentation of renal Na+ reabsorption due to a constitutively activated epithelial Na+ channel (eg, Liddle's syndrome). The presence of these latter disorders is often suggested by clinical findings of primary
mineralocorticoid excess in a patient with subnormal aldosterone levels.
Figure 10-3. Mechanisms involved in mineralocorticoid hypertension. First, there is sodium retention, fluid retention, expansion of extracellular fluid volume and plasma volume, increased cardiac output, and hypertension. Second, there is vasoconstriction and increased total peripheral resistance and hypertension. (ECFV, extracellular fluid volume.) (See text for details.)
ALDOSTERONE & THE HEART
Over the last few years, there has been increasing interest in the effects of aldosterone on the myocardium—independent of changes attributable to chronic arterial hypertension. Aldosterone excess has been shown to result in cardiac fibrosis in animals, and studies in patients with primary aldosteronism suggest that aldosterone excess is associated with alterations in myocardial texture as assessed by echocardiography. Aldosterone also appears to be important in the pathophysiology of heart failure as demonstrated by the Randomized Aldactone Evaluation Study (RALES), in which treatment with spironolactone led to a substantial reduction in morbidity and mortality in patients with severe heart failure.
Increased production of aldosterone by abnormal zona glomerulosa tissue (adenoma or hyperplasia) initiates the series of events, described in the preceding sections, that result in the typical clinical manifestations of the syndrome of primary aldosteronism. A benign aldosterone-producing adenoma, as originally described by Conn, accounts for 75% of cases of primary aldosteronism. Idiopathic hyperaldosteronism, a disorder with many similar clinical features, accounts for most of the remaining cases. In idiopathic hyperaldosteronism the adrenals are either normal in appearance or, more commonly, reveal bilateral (or, rarely, unilateral) micro- or macronodular adrenal hyperplasia.
Increased renal Na+ retention results in expansion of the extracellular fluid volume and increased total body Na+ content. Although the effects on the kidney are greatest quantitatively, other mineralocorticoid target tissues are also affected. Fecal excretion of Na+, for example, can be decreased to almost nil, with a measurable effect on the rectal potential difference. Salivary electrolyte ratios can also reflect the influence of hyperaldosteronism on that target tissue. The expanded extracellular fluid and plasma volumes are sensed by stretch receptors at the juxtaglomerular apparatus and Na+ flux at the macula densa, with resultant suppression of renin secretion, measured as suppressed plasma
renin activity. Suppression of the renin-angiotensin system, while not of itself diagnostic of primary aldosteronism, is thus a major feature of this disorder.
In addition to Na+ retention, K+ depletion develops, decreasing the total body and plasma concentration of K+. The extrusion of K+ from its intracellular reservoir is followed by the intracellular movement of H+ and, together with aldosterone-dependent increases in renal secretion of H+, results in metabolic alkalosis. With moderate K+ depletion, decreased carbohydrate tolerance (as evidenced by an abnormal glucose tolerance test) and resistance to vasopressin (as evidenced by impaired urinary concentrating ability) occur. Severe K+ depletion blunts baroreceptor function, occasionally producing postural hypotension.
Primary aldosteronism is a disease of the zona glomerulosa. Other adrenal products formed in this zone such as DOC, corticosterone, and 18-hydroxycorticosterone may be present in increased amounts in the blood or urine of persons with an aldosterone-producing adenoma (Figure 10-1). Cells of this zone do not have the ability to make cortisol (owing to the absence of the CYP17, 17α-hydroxylase system). Thus, there are no abnormalities in either cortisol production or metabolism. Plasma and urine cortisol levels are normal.
Patients typically come to medical attention because of symptoms of hypokalemia or detection of previously unsuspected hypertension during the course of a routine physical examination. The medical history reveals no characteristic symptoms other than nonspecific complaints of fatigue, loss of stamina, weakness, and lassitude—all of which are symptoms of K+ depletion. If K+ depletion is more severe, increased thirst, polyuria (especially nocturnal), and paresthesias may also be present. Headaches are frequent.
Excessive production of mineralocorticoids produces no characteristic physical findings. Blood pressure in patients with primary aldosteronism can range from borderline elevation to severely hypertensive levels. The mean blood pressure in the 136 patients reported by the Glasgow Hypertension Study unit was 205/123 mm Hg, with no significant difference between the groups with adenoma or hyperplasia. Accelerated or malignant hypertension is extremely rare. Retinopathy is mild, and hemorrhages are rarely present. Orthostatic decreases in blood pressure without reflex tachycardia are observed in the severely K+-depleted patient because of blunting of the baroreceptors. A positive Trousseau or Chvostek sign may be suggestive of alkalosis accompanying severe K+ depletion. The heart is usually only mildly enlarged, and electrocardiographic changes reflect modest left ventricular hypertrophy and K+ depletion. Clinical edema is uncommon.
Detection of spontaneous hypokalemia is often the initial clue that suggests a diagnosis of primary aldosteronism in a patient with hypertension. During the investigation, a high-K+ diet or KCl supplements should be avoided, and all previous diuretic therapy must be discontinued for at least 3 weeks before a valid serum or plasma K+ measurement can be obtained. The most common cause of hypokalemia in patients with hypertension is diuretic therapy.
In some series, up to 20% of patients with primary aldosteronism have had normal or low-normal serum K+ concentrations. Serum K+concentration is closely related to and determined to a great extent by NaCl intake (Figure 10-2). A low Na+ diet, by reducing delivery of Na+ to aldosterone-sensitive sites in the distal nephron, can reduce renal K+ secretion and thus correct hypokalemia. By the same token, increased distal delivery of Na+ accompanying a high Na+ diet can enhance K+ loss, particularly when aldosterone is being secreted autonomously and is therefore not subject to normal suppression by the high Na+ intake. These physiologic relationships serve to illustrate the importance of controlling the dietary Na+ intake when evaluating patients suspected of having primary aldosteronism. In the presence of normal renal function and autonomous aldosterone production, salt loading will usually unmask hypokalemia. Normokalemic hyperaldosteronism under these conditions has been reported but is rare.
In the USA, Japan, and many European countries, the average person consumes more than 120 mmol of Na+ per day—enough to allow hypokalemia to become manifest. If a dietary history of high salt intake is obtained and K+ concentrations are normal, a diagnosis of primary aldosteronism is unlikely. Patients who report a low Na+ intake should be advised to take an unrestricted diet plus 1 g of NaCl with each meal for 4 days; blood samples for electrolyte determinations should be obtained in the fasting state on the following morning. This dietary regimen is also useful because it prepares the patient for optimal measurement of renin and aldosterone levels.
Assessment of the renin-angiotensin system can be accomplished by a random plasma renin activity measurement.
If plasma renin activity is normal or high in a patient who has not been receiving diuretic therapy for at least 3 weeks, it is very unlikely that an aldosterone-producing adenoma is present. Some patients with idiopathic hyperaldosteronism may have low-normal levels of plasma renin activity, however. On the other hand, a subnormal plasma renin level is not alone sufficient to establish a diagnosis of primary aldosteronism, since a large subgroup of patients with essential hypertension have low plasma renin levels.
If hypokalemia and suppressed renin activity are detected, plasma and urinary aldosterone measurements should be obtained while the patient is taking an unrestricted salt diet with NaCl supplementation or if the dietary history reveals a high salt intake, as previously described. This is crucial, because with any significant diminution of salt intake, plasma aldosterone concentration and aldosterone production normally increase.
Assessment of aldosterone production can best be accomplished by measurement of urinary aldosterone excretion over a 24-hour period. Most laboratories measure excretion of the 18-glucuronide metabolite. The normal rates of urinary excretion of aldosterone-18-glucuronide range from 5 ľg to 20 ľg/24 h (14–56 nmol/24 h). In one large series, the mean values in patients with aldosterone-producing adenoma and idiopathic hyperaldosteronism were 45.2 ą 4 ľg/24 h (125 ą 9 nmol/24 h) and 27.1 ą 2 ľg/24 h (75 ą 5 nmol/24 h), respectively. Urinary measurements are superior to random measurements of plasma aldosterone for the detection of abnormal production of aldosterone but are not always able to discriminate between patients with adenoma and those with idiopathic hyperaldosteronism.
Samples for measurement of plasma aldosterone concentration should ideally be obtained at around 8:00 AM after at least 4 hours of recumbency and under the same dietary conditions as described above for measurement of urinary aldosterone. This measurement not only confirms the presence of hyperaldosteronism but also provides insight into the probable underlying pathology. When obtained under these conditions, a plasma aldosterone concentration greater than 25 ng/dL (695 pmol/L) usually indicates the presence of an aldosterone-producing adenoma (Figure 10-4).
Some investigators have advocated the use of the aldosterone:renin ratio as a means of screening for and perhaps establishing a diagnosis of primary aldosteronism. A ratio in excess of 30 (assuming that aldosterone levels are reported in nanograms per deciliter and renin levels in nanograms per milliliter per hour) is usually considered abnormal. However, since a low renin level (eg, 0.1 ng/mL/h) can result in an elevated ratio even when aldosterone levels are in the low normal range (eg, 3 ng/dL), use of the ratio in the absence of a concomitantly elevated aldosterone level should be discouraged.
Figure 10-4. Response of plasma aldosterone to postural stimulation in primary aldosteronism. (APA, aldosterone-producing adenoma; IHA, idiopathic hyperaldosteronism.)
Determining the plasma aldosterone level after 2–4 hours in the upright posture (which normally activates the renin system, with a resultant increase in the plasma aldosterone level), may be helpful in determining the cause of primary aldosteronism. Ninety percent of patients with adenoma will show no significant change or a frank decrease in plasma aldosterone levels, whereas aldosterone levels almost always increase in those with idiopathic hyperaldosteronism (Figure 10-4). The difference is due to (1) the profound suppression of the renin system by excessive aldosterone production in patients with an adenoma; (2) the influence of ACTH, to which the adenoma is still responsive and which normally decreases between 8 AM and 12 noon; and (3) decreased responsiveness of adenomas to angiotensin II. In contrast, in patients with idiopathic hyperaldosteronism, increased sensitivity of the gland to small increases in renin (and presumably of angiotensin II) levels that occur in the upright posture leads to an increased aldosterone level. Serum cortisol levels must be measured simultaneously. An increase in serum cortisol implies an ACTH discharge and invalidates the information obtained from the maneuver.
Measurement of other adrenal steroids may add to the precision of diagnosis. Plasma DOC, corticosterone, and, particularly, 18-hydroxycorticosterone levels are frequently increased in patients with adenoma, whereas they are rarely if ever increased in patients with idiopathic hyperaldosteronism. Increased
urinary excretion of 18-hydroxycortisol and 18-oxocortisol, which is a characteristic finding in individuals with the dexamethasone-suppressible form of primary aldosteronism (described in a subsequent section), may also be present in some patients with aldosterone-producing adenomas.
The procedures just discussed can confirm a diagnosis of primary aldosteronism and differentiate adenoma from idiopathic hyperaldosteronism in most cases. Localization studies can also provide additional information. When uncertainty persists, the saline infusion test may also be useful.
Saline loading establishes aldosterone unresponsiveness to volume expansion and thereby identifies autonomy in patients with aldosterone-producing adenomas. Two liters of isotonic NaCl are administered over 2–4 hours. Blood samples for aldosterone and cortisol measurements are obtained before and after the infusion. Expansion of the extracellular fluid volume reduces plasma aldosterone concentration promptly in patients with “essential” hypertension but fails to suppress plasma aldosterone concentration into the normal range in patients with adenoma or hyperplasia. Moreover, the saline infusion test typically distinguishes patients with primary aldosteronism from those with low-renin essential hypertension. The ratio of aldosterone to cortisol is typically greater than 3.0 following administration of saline in patients with an aldosterone-producing adenoma, reflecting the limited effect of volume expansion in the setting of marked suppression of the renin-angiotensin system.
Rare Forms of Primary Aldosteronism
Dexamethasone-remediable aldosteronism is a rare form of genetic hypertension that has been recognized with increasing frequency since the molecular basis of this disorder was established. It is inherited in an autosomal dominant fashion. The primary defect is a gene duplication that results from an unequal crossing over event that fuses the regulatory region of the 11β-hydroxylase gene to the coding sequence of aldosterone synthase. This chimeric gene leads to ACTH-dependent expression of aldosterone synthase in the zona fasciculata, thereby resulting in the synthesis of aldosterone, 18-hydroxycortisol, and 18-oxocortisol (phenotypic markers of this disorder). Patients present with hypertension and biochemical features of mineralocorticoid excess (eg, suppressed plasma renin activity, increased aldosterone secretion) which are ameliorated with glucocorticoid administration. However, the response to dexamethasone suppression may dissipate over the long term in many patients, and additional antihypertensive therapy may thus be necessary. The presence of glucocorticoid-remediable aldosteronism should be considered in any family in which more than one individual is found to have primary aldosteronism. The diagnosis can easily be established by measurement of the marker steroids (18-oxocortisol or 18-hydroxycortisol) or by detection of the abnormal gene in DNA samples obtained from peripheral blood leukocytes.
Malignant adrenocortical tumors producing aldosterone in the absence of hypercortisolism are rare, accounting for less than 3% of cases of primary aldosteronism. In general, the biochemical and hormonal features and the response to dynamic tests are similar to those typical in adenoma except that the magnitude of the abnormalities is usually greater. Hypercortisolism as well as hyperandrogenism or hyperestrogenism may occur during the progression of the disease.
Management of Aldosterone-Producing Adenomas
Once the biochemical diagnosis is secure, procedures that identify the likely site of an adenoma can aid in establishing the appropriate surgical approach. A number of techniques have been developed including adrenal venography, adrenal scintigraphy, adrenal vein catheterization with sampling for aldosterone measurements, and CT or MRI imaging. The diagnostic information provided by CT scanning or MRI in locating adenomas has proved to be both accurate and practical and is the initial procedure of choice. Adrenal venography was associated with a number of problems, such as extravasation of dye, hemorrhage, and adrenal infarction and is no longer utilized. Scanning using intravenously administered 131I-iodocholesterol can identify the site of an adenoma in about 80% of patients, although the success rate decreases markedly if tumors are less than 1 cm in diameter. The procedure takes several visits to accomplish, however. The use of131I-labeled 6β-iodomethyl-19-norcholesterol reduces the interval between injection and scintiscanning to about 3–7 days.
Patients suspected of having an aldosterone-producing adenoma (younger age, more severe hypertension, more profound hypokalemia, and higher aldosterone secretion) who are found to have a unilateral adrenal nodule greater than 1 cm should proceed to unilateral laparoscopic adrenalectomy. Patients with less severe
biochemical findings may have idiopathic hyperaldosteronism with an adrenal incidentaloma. For such patients and for those with equivocal CT findings (eg, adrenal nodules < 1 cm or bilateral adrenal abnormalities), adrenal vein sampling provides the most accurate means of differentiating a unilateral aldosterone-producing adrenal adenoma from idiopathic hyperaldosteronism.
Adrenal vein catheterization to obtain samples for measurement and comparison of aldosterone levels in the venous effluent of both adrenal glands continues to be useful in lateralizing tumors after other techniques fail and biochemical evidence still supports the diagnosis of adenoma. The success of this procedure is highly dependent on the skill and experience of the interventional radiologist. Cortisol levels should always be measured simultaneously to confirm the source of the sample and the extent of contamination with nonadrenal venous blood. Treatment with ACTH prior to and during the study (cosyntropin, 50 ľg/h, given as a continuous infusion initiated 30 minutes prior to the study) is also recommended to magnify the differences between affected and unaffected sides and to avoid variable ACTH stimulation during the procedure. An adrenal vein to inferior vena cava cortisol gradient greater than 5:1 generally confirms successful adrenal vein catheterization. When comparing adrenal vein samples, the aldosterone level should be corrected for dilutional effects by dividing by the cortisol level. The finding of a ratio of the adrenal vein aldosterone levels so corrected that exceeds 4:1 is consistent with a unilateral aldosterone-producing adenoma.
Treatment depends for the most part on the accuracy of diagnosis. In patients with an aldosterone-producing adenoma and no contraindication to surgery, unilateral adrenalectomy is recommended. The degree of reduction of blood pressure and correction of hypokalemia achieved with prior spironolactone therapy provides a good indication of the likely response to surgery; in fact, greater reduction often occurs postoperatively, presumably because of a greater reduction of extracellular fluid volume. The surgical cure rate of hypertension associated with adenoma is excellent—more than 70% have benefited in several large series—with reduction of hypertension in the remainder.
Subtotal adrenalectomy will correct hypokalemia in patients with idiopathic aldosteronism, but hypertension is rarely cured. Therefore, other antihypertensive measures (including spironolactone) should be used to control hypertension, and such patients should not be routinely sent to surgery. A subset of patients with primary aldosteronism but no identifiable adenoma may benefit from surgical reduction of adrenal mass, ie, subtotal or total adrenalectomy. This group (referred to as primary adrenal hyperplasia) typically responds to stimulatory and suppressive maneuvers in a manner similar to patients with an aldosterone-producing adenoma. Pathologic examination of the adrenal tissue usually discloses micro- or macronodular hyperplasia. The autonomy of aldosterone production in this condition is difficult to explain, but the disease may be compared to the autonomy of cortisol production in nodular dysplasia associated with Cushing's syndrome.
Ideally, patients should be treated preoperatively with spironolactone until the blood pressure and serum K+ are normal. This drug is particularly beneficial because of its unique mechanism of action in blocking the mineralocorticoid receptor. Spironolactone reduces the volume of the expanded extracellular fluid toward normal, promotes K+ retention, and restores normal serum K+ concentration. It often has the additional desirable effect of activating (after 1–2 months) the suppressed renin-angiotensin system and, consequently, of aldosterone secretion by the contralateral adrenal gland. Postoperative hypoaldosteronism with hyperkalemia is unlikely with this treatment. Preoperative treatment will also permit reversal to some extent of some of the changes in target organs that were produced by the hypertensive and hypokalemic states. Spironolactone is usually well tolerated; the side effects of rashes, gynecomastia, impotence, and epigastric discomfort are rare over a short time interval. Once blood pressure and serum K+ levels are normal on an initial dose of 200–300 mg/d, the dose can be tapered to a maintenance dose of approximately 100 mg/d until the time of surgery. In patients who develop one or more of these side effects, the K+-sparing diuretic amiloride, in doses of 20–40 mg/d, can be used as an alternative. Other antihypertensive drugs may also be required and should be used to obtain optimal blood pressure control. Calcium channel blockers appear to be effective in this setting.
When the diagnosis and lateralization are certain, surgical removal of the adenoma is advised. Current preoperative lateralization techniques easily identify the site of tumor, which can be removed via a laparoscope in virtually all cases.
Over 70% of patients with primary aldosteronism who have undergone surgery have had unilateral adenoma. Bilateral tumors are rare. The characteristic adenoma is readily identified by its golden-yellow color. In addition, small satellite adenomas are often found, and distinction from micro- or macronodular hyperplasia is
occasionally difficult. In patients with adenoma, the contiguous adrenal gland can show hyperplasia throughout the gland. Hyperplasia is also present in the contralateral adrenal gland but is not associated with aldosterone abnormalities after removal of the primary adenoma.
If the tumor is identified at surgery in a patient who had a unilateral lesion detected preoperatively, exploration of the contralateral adrenal is not indicated. If surgery is contraindicated or refused, prolonged treatment with spironolactone can be effective. The initial dose of 200–400 mg of spironolactone per day must be continued for 4–6 weeks before the full effect on blood pressure is realized. With prolonged treatment, aldosterone production does not increase even though K+ replenishment and activation of the renin-angiotensin system occur. In addition, spironolactone directly inhibits aldosterone synthesis by adenomas. A chronic dose of 75–100 mg is usually sufficient to maintain a normal blood pressure.
Patients who have had unilateral adrenalectomy for removal of an aldosterone-producing tumor occasionally have a transient period of relative hypomineralocorticoidism with negative Na+ balance, K+ retention, and mild acidosis. Full recovery of the chronically unstimulated, contralateral zona glomerulosa usually takes place in 4–6 months following surgery but may take longer. Restitution of the suppressed renin-angiotensin system to normal is required for a completely normal adrenocortical response similar to the need for recovery of pituitary function after removal of a cortisol-producing adenoma (Cushing's syndrome). No specific treatment is usually necessary other than adequate Na+ intake. A small percentage of patients (1%) do not have normal recovery of their renin-angiotensin-aldosterone system and require mineralocorticoid replacement (fludrocortisone) therapy for life. Preexisting renal disease that impairs renin secretion is usually evident in such individuals.
SYNDROMES DUE TO EXCESS DEOXYCORTICOSTERONE PRODUCTION
Deoxycorticosterone is the second most important naturally occurring mineralocorticoid hormone. Accordingly, excess DOC production should be suspected in any hypertensive patient with hypokalemia and suppression of renin and aldosterone production.
17α-Hydroxylase deficiency syndrome is usually recognized at the time of puberty in young adults by the presence of hypertension, hypokalemia, and primary amenorrhea (with sexual infantilism) in the female or pseudohermaphroditism in the male (Chapter 14). In contrast to the clinical manifestations in 21- and 11β-hydroxylation deficiencies, there is no virilization or restricted growth. Patients often present with eunuchoid proportions and appearance. The virtual absence of 17α-hydroxyprogesterone, pregnanetriol, and 17-ketosteroids is diagnostic of this type of hydroxylase deficiency.
The key location of the 17α-hydroxylating system (cytochrome P450c17α) in the steroid biosynthetic pathway prevents normal production of androgens and estrogens (Figure 9-4). There has been no instance in which the adrenal defect has appeared without a concomitant gonadal defect. The defect occurs in a single gene (in chromosome 10), which codes for the enzyme or the expression of the enzyme. The diminution of cortisol production induces increased production of ACTH. Initially, activity of the entire biosynthetic pathway of non-17-hydroxylated steroids is increased—namely, progesterone, DOC, corticosterone, 18-hydroxydeoxycorticosterone, 18-hydroxycorticosterone, and aldosterone. Subsequently, expansion of extracellular fluid and blood volumes, hypertension, and profound suppression of the renin-angiotensin system results, in most cases, in reduced aldosterone levels. Thus, the principal steroids present in excess are DOC, corticosterone, 18-hydroxycorticosterone, and 18-hydroxydeoxycorticosterone.
Congenital adrenal hyperplasia due to 11β-hydroxylase deficiency is usually recognized in newborns and infants because of virilization and the presence of both hypertension and hypokalemia. Plasma androgens, 11-deoxycortisol, 17α-hydroxyprogesterone, urinary 17-ketosteroids, and 17-hydroxycorticosteroids are increased. (See Chapter 14 and Figure 14-14.)
The defect in the gene (mapped to chromosome 8) is usually partial, so that some cortisol is produced, but it does not increase with further stimulation by ACTH. Blood levels and production rates of cortisol are usually within normal limits. A partial defect of 11β-hydroxylation results in increased production and blood levels of DOC, 11-deoxycortisol (Figure 10-1), and androgens. Hypertension results from excessive production of DOC by mechanisms similar to those previously described for aldosterone.
The blood levels and production rates of aldosterone are low-normal or reduced. Two mechanisms are proposed. Originally, a partial deficiency of the 11β-hydroxylation activity in the zona glomerulosa was postulated, with a block in aldosterone synthesis. This
concept was supported by the observation that after normalization of DOC production and correction of the hypertension (by ACTH suppression), aldosterone production remained normal or reduced and a Na+-losing state could be provoked. Currently, it is felt that there is no zona glomerulosa defect but that suppression of renin by the increased production of DOC reduces the production of aldosterone in the zona glomerulosa. Thus, after chronic salt restriction and ACTH suppression, both renin and aldosterone dynamics return to normal, implying an intact zona glomerulosa.
Treatment of 17α- & 11β-Hydroxylase Deficiency
Treatment of both of these disorders is similar to that of all non-Na+-losing forms of congenital adrenal hyperplasia. Treatment with physiologic replacement doses of glucocorticoid, such as hydrocortisone or dexamethasone, restores blood pressure to normal levels, corrects K+ depletion, reduces excessive DOC and corticosterone production in 17α-hydroxylase deficiency, and reduces DOC and 11-deoxycortisol production in 11β-hydroxylase deficiency. In 17α-hydroxylase deficiency syndrome, restoration of normal levels of DOC results in a return of plasma renin activity and aldosterone to normal values. A delay in return of the suppressed renin-aldosterone system toward normal can result in hypovolemic crises with the initial natriuresis and diuresis. It may take several years before the aldosterone and renin systems become normal. The amount of glucocorticoid administered must be carefully determined because of apparently exquisite tissue sensitivity to glucocorticoid hormones. Addition of estrogen-progestin combined cyclic therapy may be necessary in the adult patient with 17α-hydroxylase deficiency (see Chapter 14).
Androgen- & Estrogen-Producing Adrenal Tumors
Most of the C-19 steroids produced by the adult adrenocortical zona reticularis have weak androgen activity, especially dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) as well as androstenedione. Disturbances in both internal zona reticularis regulatory mechanisms (ie, enzyme activity) and its extra-adrenal regulators (ACTH and an androgen-stimulating peptide of possible hypothalamic-pituitary origin) may lead to excessive adrenal sex steroid production, resulting in syndromes of hirsutism and virilization in the female or feminization in men.
Although the zona reticularis has no intrinsic capacity to synthesize any effective glucocorticoid or mineralocorticoid, it has the potential, under conditions of chronic stimulation by ACTH, to transform some cellular function into the fasciculata cell type (by the induction of specific enzyme complexes) and produce cortisol and presumably other typical zona fasciculata steroids.
Some patients with malignancies originating in the zona reticularis (androgen- or estrogen-producing tumors, or both types) may have clinical features of mineralocorticoid excess, with hypertension, hypokalemia, and renin suppression. Aldosterone levels are generally not elevated and are often reduced. Urinary or plasma steroid profiling in some of these patients suggests that there may be inhibition of 11β-hydroxylase activity in association with the increased production of androgens or estrogens. Administration of methylandrostanediol to experimental animals and testosterone to humans suggests that exogenous androgen excess can block the conversion of 11-deoxycortisol and DOC to cortisol and corticosterone, respectively. Excessive secretion of DOC could then lead to a state of mineralocorticoid excess. Increased urinary excretion of DOC metabolites or plasma DOC concentrations have been found in several patients with androgen- or estrogen-producing adrenocortical carcinomas who have hypertension and hypokalemia.
The inhibition of 11β-hydroxylase in these carcinomas may be due to inactivation of the enzyme cytochrome CYP11B1 (formerly P450c11) by the high intra-adrenal concentration of androgens (androstenedione) that act as a pseudosubstrate for the reaction. This mechanism is similar to that occurring in Cushing's syndrome, in which cortisol appears to serve as the enzymatic inhibitor.
Syndrome of Primary Cortisol Resistance
Peripheral resistance to cortisol action is a very rare condition—reported only in a few families—in which hypertension, hypokalemia, and renin suppression are associated with elevated plasma and urinary levels of cortisol without causing clinical manifestations of Cushing's syndrome. The basic defect is at the level of the glucocorticoid receptor; both the number of receptors and the affinity of the receptors for cortisol are reduced in the target tissues. In this condition, plasma levels of ACTH are elevated as a result of block of cortisol feedback at the corticotroph. Cortisol production is thus increased, but it does not result in the typical clinical stigmas of hypercortisolism. However, chronic stimulation by excess ACTH of the 17-deoxy pathway of the zona fasciculata results in abnormal production of DOC and corticosterone, causing hypertension, hypokalemia, and suppression of renin and aldosterone production. Adrenal androgen production also increases under ACTH stimulation, and affected women may present with hirsutism, menstrual irregularities,
and virilization. The clinical and biochemical abnormalities are partially relieved by treatment with high doses of dexamethasone.
Hypertension is a common finding of endogenous hypercortisolism (present in more than 80% of cases; see Chapter 9) but occurs in only 10–20% of patients receiving therapy with synthetic glucocorticoids. ACTH-dependent hypercortisolism (Cushing's disease and ectopic ACTH production) is frequently accompanied by increased levels of other ACTH-dependent steroids, especially DOC and corticosterone. Elevated DOC (Figure 10-5) and cortisol levels probably contribute to the mineralocorticoid excess state. Plasma renin activity varies but is typically normal as a consequence of concomitant increase in the production of angiotensinogen. Serum K+ levels are also normal in most patients, implying the absence of a mineralocorticoid excess state. However, a small subset of patients have hypokalemia and suppressed plasma renin levels. Most of these patients have ectopic ACTH hypersecretion or adrenal tumors. Even when there is evidence for mineralocorticoid excess (suppressed plasma renin and hypokalemia), levels of aldosterone and 18-hydroxycorticosterone are consistently within or below the low normal range.
Figure 10-5. Basal cortisol, deoxycorticosterone, and aldosterone levels in patients with Cushing's syndrome according to etiology.
Hypertension in Cushing's syndrome is usually more frequent in patients with adrenocortical hyperplasia (due to ACTH excess) than in patients with cortical adenomas, which implies that, in addition to cortisol, other ACTH-dependent steroids (eg, DOC, corticosterone, or 18-hydroxydeoxycorticosterone) may contribute to the development or maintenance of hypertension. In addition, urinary excretion of the potent naturally occurring mineralocorticoid 19-nor-DOC, produced in the kidney by the conversion of an oxygenated form of DOC, is elevated in both the primary (adrenal) and secondary (pituitary) forms of Cushing's syndrome.
Since most patients with Cushing's syndrome do not have findings consistent with hypermineralocorticoidism (eg, hypokalemia and hyporeninemia), glucocorticoids appear to cause hypertension by mineralocorticoid-independent mechanisms (Figure 10-6). These include increased production of angiotensin II due to glucocorticoid-induced increases in the hepatic synthesis of angiotensinogen; enhanced glucocorticoid-mediated vascular reactivity to vasoconstrictors; inhibition of extraneuronal uptake and degradation of catecholamines; inhibition of vasodilatory systems such as kinins and prostaglandins; shift in Na+ from the intracellular to the extracellular compartment, resulting in increased plasma volume; and an increase in cardiac output from the increased production of epinephrine
due to enhanced phenylethanolamine-N-methyltransferase activity in the adrenal medulla.
Figure 10-6. Mechanisms involved in glucocorticoid hypertension. (DOC, deoxycorticosterone; MCH, mineralocorticoid hormone; ECFV, extracellular fluid volume; ICFV, intracellular fluid volume; PRC, plasma renin concentration; PRA, plasma renin activity; COMT, catechol-O-methyltransferase; PNMT, phenylethanolamine-N-methyltransferase.)
The term pseudohyperaldosteronism comprises a heterogeneous group of disorders in which the clinical features are consistent with mineralocorticoid excess yet endogenous mineralocorticoid secretion is abnormally low owing to suppressed renin production. Renin secretion is suppressed by increased Na+ retention and volume expansion, resulting either from the presence of endogenous or exogenous mineralocorticoids or mineralocorticoid-like substances or from a mineralocorticoid-independent increase in renal tubular sodium transport. Hypertension, hypokalemia, and metabolic alkalosis are the usual manifestations. In addition to the syndromes that result from excess production of DOC as described above, continuous use of fluorinated steroids with powerful mineralocorticoid-like activity contained in some topical preparations such as nasal sprays and dermatologic creams can be associated with hypertension, hypokalemia, and renin and aldosterone suppression. Withdrawal of these medications or adjustment of the dosage easily controls undesirable side effects. Pseudohyperaldosteronism can also occur as a prominent feature of several rare syndromes, the pathophysiologic features of which have only recently been established. These are described in the following sections.
Syndrome of Apparent Mineralocorticoid Excess (11β-Hydroxysteroid Dehydrogenase Deficiency)
A rare disorder, initially designated as the syndrome of apparent mineralocorticoid excess, is characterized by findings suggestive of a hypermineralocorticoid state (hypertension, hypokalemia, suppressed renin levels, and amelioration by spironolactone) despite low levels of aldosterone and DOC. Most of the reported cases have been in children who have severe—often lethal—hypertension. Although the pathogenesis remained elusive for more than a decade, it is now evident that the primary abnormality in this disorder is reduced peripheral metabolism of cortisol due to a mutation in the gene encoding 11β-hydroxysteroid dehydrogenase type 2, the isoenzyme that is present in greatest abundance in the renal tubule. Impaired conversion of cortisol to cortisone (Figure 10-7) in the cells of the renal tubule
results in an accumulation of cortisol and subsequent occupancy of mineralocorticoid receptors. Despite normal plasma cortisol levels, urinary cortisol is increased, reflecting impairment of the kidney's ability to convert cortisol to cortisone. The increased urinary excretion of tetrahydrocortisol (THF) and reduced excretion of tetrahydrocortisone (THE) leads to a marked increase in the THF/THE ratio (Figure 10-8), a finding considered diagnostic of this disorder. Treatment consists of the administration of small doses of dexamethasone (0.75–1 mg/d) to suppress ACTH and to limit thereby the production of cortisol and its accumulation in mineralocorticoid target tissues in the kidney.
Figure 10-7. Principal pathways of cortisol metabolism. (11β-OHSD, 11β-hydroxysteroid dehydrogenase; DHF, dihydrocortisol; THF, tetrahydrocortisol; THE, tetrahydrocortisone.)
Chronic Ingestion of Licorice
Chronic ingestion of large amounts of substances containing “mineralocorticoid-like activity”—eg, certain candies, infusions, and some chewing tobaccos containing licorice—results in a syndrome of hypertension, hypokalemia, renal Na+ retention, volume expansion, suppressed plasma renin activity, and metabolic alkalosis. Aldosterone secretion and excretion are low or undetectable, however, as are other mineralocorticoid precursors in the aldosterone pathway. The responsible agent for this syndrome is the active principle of licorice, glycyrrhizic acid, and its metabolite glycyrrhetinic acid, that are present in certain commercially available products. Both of these alkaloids inhibit 11β-hydroxysteroid dehydrogenase in the kidney, which increases free cortisol locally to act as the mineralocorticoid in a manner similar to the syndrome of apparent mineralocorticoid excess. Pseudohyperaldosteronism can be induced by licorice and its derivatives such as carbenoxolone (an anti-gastric ulcer drug), the Na+ hemisuccinate of 18β-glycyrrhetinic acid. Electrolyte
abnormalities and hypertension disappear within a few weeks upon discontinuation of licorice ingestion or withdrawal of carbenoxolone treatment.
Figure 10-8. Ratio of the urinary metabolites of cortisol (THF, tetrahydrocortisol; 5α-THF, allotetrahydrocortisol) to cortisone (THE, tetrahydrocortisone) in the syndrome of apparent mineralocorticoid excess. (Modified from Shackleton CHL, Stewart PM: The hypertension of apparent mineralocorticoid excess syndrome. In: Endocrine Hypertension. Biglieri EG [editor]. Raven Press, 1990.)
In 1963, Liddle and colleagues reported the results of studies in a large family in which the affected members had clinical manifestations resembling those of classic primary aldosteronism: hypertension, hypokalemia with renal K+ wasting, metabolic alkalosis, and suppressed plasma renin activity. Aldosterone production, however, was negligible. The inheritance pattern in this large family was that of an autosomal dominant disorder, and the phenotype was soon identified in several additional families as well as in sporadic cases.
Although these findings suggested the possibility of excessive production of another mineralocorticoid to explain the clinical manifestations, in contrast to patients with excess DOC production or those with the syndrome of apparent mineralocorticoid excess, administration of the mineralocorticoid antagonist spironolactone did not correct either the hypertension or the hypokalemia. Furthermore, the adrenocortical synthesis-blocking agent metyrapone, which inhibits 11β- and 18-hydroxylation of aldosterone precursors, also had no effect. In contrast, administration of triamterene, a diuretic agent with K+-sparing activity independent of mineralocorticoid antagonism, was effective in correcting the abnormalities. The investigators proposed that a primary abnormality in the renal tubule that enhanced Na+ reabsorption was responsible.
Recent studies in the original kindred of Liddle as well as in individuals from several other kindreds similarly affected proved this hypothesis to be remarkably prescient. Using linkage analysis as well as electrophysiologic techniques, it has been established that patients with Liddle's syndrome have a defect in the cytoplasmic domain of either the β or γ subunit of the epithelial Na+ channel that results in constitutive activation of the channel. Since amiloride as well as triamterene are relatively specific inhibitors of this channel, treatment with these agents will correct the electrolyte abnormalities and ameliorate the hypertension as well.
TYPE II PSEUDOHYPOALDOSTERONISM (Arnold-Healy-Gordon Syndrome)
The term type II pseudohypoaldosteronism has been used to describe a rare autosomal dominant clinical syndrome in which hypertension is present in association with hyperkalemia, impairment of renal K+ excretion, hyperchloremic metabolic acidosis, and hyporeninemic hypoaldosteronism. The glomerular filtration rate (GFR) is usually normal. Mineralocorticoid resistance is apparent by persistence of hyperkalemia and a subnormal kaliuretic response to large doses of exogenously administered mineralocorticoid hormone. However, in contrast to patients with the classic form of mineralocorticoid resistance (type I pseudohypoaldosteronism), salt wasting is not present and both the antinatriuretic and antichloruretic responses to mineralocorticoid are intact.
An impairment in renal K+ secretion was initially proposed as the primary defect. However, whereas fractional renal K+ excretion was subnormal and increased only minimally when Na+ was delivered to distal nephron segments as NaCl, distal renal K+ secretion increased greatly when Na+ was delivered distally in the presence of non-Cl- anions (sulfate and bicarbonate). These findings indicate that the renal K+ secretory mechanism is intact and suggest that the primary defect is related to increased Cl- reabsorption in the distal nephron. This, in turn, would (1) limit the Na+ and mineralocorticoid-dependent driving force for K+ and H+ secretion, resulting in hyperkalemia and acidosis; and (2) augment distal NaCl reabsorption, resulting in hyperchloremia, volume expansion, and hypertension. Consistent with the presence of such a “chloride shunt,” restriction of dietary NaCl or administration of a chloruretic diuretic (furosemide, thiazides) ameliorates hyperkalemia and acidosis in such patients. It is now known that two separate mutations in the WNK
family of serine-threonine kinases (WNK 1 and WNK 4) are responsible for type II pseudohypoaldosteronism. Both kinases localize to distal nephron segments known to play a key role in the transport of ions that are altered in this syndrome.
HYPERTENSION OF RENAL ORIGIN
THE RENIN-ANGIOTENSIN SYSTEM
The term “renin” was first suggested by Tigerstedt and Bergman in 1898 to denote the pressor material in saline extracts of rabbit kidneys. Pioneer studies by Page and Helmer and Braun-Menendez in the 1930s demonstrated that renin enzymatically cleaves an α2-globulin substrate (angiotensinogen) to form a decapeptide (angiotensin I) that is subsequently cleaved by angiotensin-converting enzyme (ACE) to form an octapeptide (angiotensin II) with potent vasoconstrictor effects. During this same period, Goldblatt noted that reducing the flow of blood to the kidney in experimental animals was followed by an increase in blood pressure. Subsequently, these two landmark observations were found to be related; reducing blood flow to the kidney stimulates the renin-angiotensin system, resulting in an increase in blood pressure. The integration of these concepts is a key paradigm in understanding blood pressure regulation and has served as one of the important models in evaluating mechanisms of hypertension.
As the afferent arteriole enters the glomerulus (Figure 10-9), the smooth muscle cells become modified to perform a secretory function. These juxtaglomerular cells produce and secrete renin, a proteolytic enzyme with a molecular weight of approximately 40,000. In close proximity to the juxtaglomerular cells are specialized tubular cells of the cortical thick ascending limb of the loop of Henle known as the macula densa. The juxtaglomerular cells of the afferent arteriole and the macula densa are referred to collectively as the juxtaglomerular apparatus and the interplay of these specialized cells has an important role in the regulation of renin secretion.
The synthesis of renin involves a series of steps beginning with the translation of renin mRNA into preprorenin. The 23-amino-acid amino terminal sequence of preprorenin directs trafficking of the protein into the endoplasmic reticulum, where it is subsequently cleaved, resulting in the formation of prorenin. Prorenin is glycosylated in the Golgi apparatus and is either secreted directly into the circulation by a nonregulated constitutive pathway or is processed in secretory granules to form active renin. Although prorenin constitutes 50–90% of the total circulating renin, it has no clear physiologic role. Prorenin can be converted into renin in vitro by a number of methods, but it is unlikely that significant extrarenal conversion of prorenin occurs in vivo. Plasma prorenin levels tend to be elevated in patients with type 1 diabetes mellitus in association with microvascular complications.
Figure 10-9. Diagram of a glomerulus, showing juxtaglomerular apparatus and macula densa.
The release of renin from secretory granules into the circulation is controlled by three major effectors: (1) baroreceptors in the wall of the afferent arteriole that are stimulated by decreases in renal arteriolar perfusion pressure, perhaps mediated by local production of prostaglandins; (2) cardiac and systemic arterial receptors that activate the sympathetic nervous system, resulting in increased circulating catecholamines and increased direct neural stimulation of juxtaglomerular cells via β1-adrenergic receptors; and (3) cells of the macula densa that appear to be stimulated by a reduction in Na+ or Cl- ion concentrations in the tubular fluid delivered to this site. The Cl- ion may be the primary mediator of this effect.
Once secreted, renin initiates a series of steps beginning with the enzymatic cleavage of a decapeptide, angiotensin
I from the amino terminal of angiotensinogen. Angiotensin I is then converted to the octapeptide angiotensin II (Figure 10-10) by angiotensin-converting enzyme (ACE). The concentration of ACE is greatest in the lung. It is also localized to the luminal membrane of vascular endothelial cells, the glomerulus, the brain, and other organs. The half-life of angiotensin II in plasma is less than 1 minute as a result of the action of multiple angiotensinases located in most tissues of the body.
Angiotensinogen (renin substrate) is an α2-globulin secreted by the liver. It has a molecular weight of approximately 60,000 and is usually present in human plasma at a concentration of 1 mmol/L. Although the rate of production of angiotensin II is normally determined by changes in plasma renin concentration, the concentration of angiotensinogen is below the Vmax for the reaction. Thus, if angiotensinogen concentration increases, the amount of angiotensin produced at the same plasma renin concentration will increase. As will be discussed later, increased levels of angiotensinogen have been noted in patients with essential hypertension, and there appears to be linkage between a variant allele for the angiotensinogen gene and the presence of essential hypertension in selected populations. Hepatic production of angiotensinogen is increased by glucocorticoids and by estrogens. Stimulation of angiotensinogen production by estrogen-containing contraceptive pills may contribute to some of the hypertension encountered as a side effect of this treatment.
In situations such as Na+ depletion, where there is a sustained high circulating level of renin, the rate of breakdown of angiotensinogen is greatly increased. Because the plasma concentration of angiotensinogen remains constant in these situations, hepatic production must increase to match the increased rate of breakdown. The mechanism of this increase is not clear, though angiotensin II itself is known to be a stimulus to angiotensinogen production.
Angiotensin-converting enzyme is a dipeptidyl carboxypeptidase, a glycoprotein of MW 130,000–160,000, that cleaves dipeptides from a number of substrates. In addition to angiotensin I, these include bradykinin, enkephalins, and substance P. Inhibitors of ACE are widely used to prevent the formation of angiotensin II in the circulation and thus block its biologic effects (Figure 10-10). Since ACE acts on a number of substrates, blockade of the enzyme may not always exert its effects solely via the renin-angiotensin system. In fact, the increased kinin levels caused by inhibitors of ACE may contribute to the hypotensive action of this class of drugs by releasing nitric oxide from vascular endothelial cells. Bradykinin antagonists can blunt the hypotensive effect of ACE inhibitors. Increased
kinins may contribute to another effect of ACE inhibitors—ie, the ability to improve insulin sensitivity—which can lower the blood glucose in patients with type 2 diabetes. In addition, the accumulation of kinins may account for two of the most significant side effects of ACE inhibitors: cough, angioedema, and anaphylaxis.
Figure 10-10. The renin-angiotensin-aldosterone axis. Angiotensin II is a critical hormone in the control of blood pressure.
In addition to ACE, a serine protease known as chymase has been shown to convert angiotensin I to angiotensin II. This enzyme has been identified in various tissues, most notably the cardiac ventricles. Thus, there appears to be an ACE-independent pathway for the production of angiotensin II.
Similar to other peptide hormones, angiotensin II binds to receptors on the plasma membrane of target cells. Two major classes of angiotensin II receptors (AT1 and AT2) have been characterized and their respective mRNAs isolated and cloned. AT1 appears to mediate virtually all the known cardiovascular, renal, and adrenal-stimulatory effects of angiotensin II; AT2 may be involved in cell differentiation and growth. Both receptors have a seven-transmembrane-spanning motif. AT1 is linked to a G protein that activates phospholipase C, resulting in the hydrolysis of phosphoinositide to form inositol triphosphate and diacylglycerol. Generation of these second messengers results in a cascade of intracellular events including increases in calcium concentration, activation of protein kinases, and perhaps decreases in intracellular cAMP. The precise signaling mechanism associated with the AT2 receptor is still unknown.
Angiotensin II is a potent pressor agent, exerting its effects on peripheral arterioles to cause vasoconstriction and thus increasing total peripheral resistance. Vasoconstriction occurs in all tissue beds, including the kidney, and has been implicated in the phenomenon of renal autoregulation. Angiotensin may also increase the rate and strength of cardiac contraction. The possible role of increased circulating levels of angiotensin II in the pathogenesis of hypertension is discussed below.
Angiotensin II also acts directly on the adrenal cortex to stimulate aldosterone secretion and in most situations is the most important regulator of aldosterone secretion. Angiotensin thus plays a central role in regulating Na+ balance. For example, during dietary Na+depletion, extracellular fluid volume is reduced. Subsequent stimulation of the renin-angiotensin system is important in two ways: Its vasoconstrictor actions help to maintain blood pressure in the face of reduced extracellular fluid volume, whereas its actions to stimulate aldosterone secretion and thus Na+ retention allow volume to be conserved.
During chronic intravascular volume depletion, such as occurs during a low Na+ intake, the persistent increases in angiotensin II levels results in AT1 receptor down-regulation in the vasculature. In this setting, there is less vasoconstriction for a given plasma level of angiotensin II. In contrast, intravascular volume depletion increases the number of AT1 receptors in the adrenal glomerulosa, resulting in augmented aldosterone secretion. It has been suggested that these opposite and apparently contradictory effects of chronic intravascular volume depletion on responsiveness of the vasculature and the adrenal glomerulosa to angiotensin II may be physiologically appropriate; in the setting of a low-Na+ diet, the greater increase in aldosterone secretion allows Na+ reabsorption to occur without a major rise in blood pressure. As will be discussed later, this so-called “Na+ modulation” of adrenal and vascular responsiveness to angiotensin II may be modified in some patients with essential hypertension.
Angiotensin II modulates activity at sympathetic nerve endings in peripheral blood vessels and in the heart. It increases sympathetic activity partly by facilitating adrenergic transmitter release and partly by increasing the responsiveness of smooth muscle to norepinephrine. Angiotensin II also stimulates the release of catecholamines from the adrenal medulla.
A number of angiotensin receptor antagonists or blockers (ARBs) have been developed. The current clinically available ARBs only reduce AT1 activity—there is no change in AT2 receptor-mediated effects. In contrast, inhibition of angiotensin II formation with an ACE inhibitor will diminish the activity of both receptor subtypes. The ARBs do not directly affect bradykinin levels. Given that ACE inhibitors may reduce blood pressure in part by augmenting bradykinin levels and that angiotensin II formation can occur despite ACE inhibition, combination ACE inhibitor and ARB therapy may have an additive effect in lowering blood pressure. Clinical trials are currently investigating whether combination ACE inhibitor and ARB therapy confers additional benefit for lowering blood pressure and preventing end-organ damage.
Blockade of the formation or peripheral effects of angiotensin II is useful therapeutically. For example, in low-output congestive cardiac failure, plasma levels of angiotensin II are high. These high circulating levels promote salt and water retention and, by constricting arterioles, raise peripheral vascular resistance, thus increasing cardiac afterload. Treatment with ACE inhibitors or ARBs results in peripheral vasodilation, thereby improving tissue perfusion and cardiac performance as well as aiding renal elimination of salt and water. The use of ACE inhibitors as well as of AT1 receptor antagonists in the treatment of hypertension is discussed in a subsequent section.
Effects of Angiotensin II in the Brain
Angiotensin II is a polar peptide that does not cross the blood-brain barrier. Circulating angiotensin II, however, may affect the brain by acting through one or more of the circumventricular organs. These specialized regions within the brain lack a blood-brain barrier, so that receptive cells in these areas are sensitive to plasma composition. Of particular significance to the actions of angiotensin are the subfornical organ, the organum vasculosum of the lamina terminalis, and the area postrema. (See Chapter 5 and Figure 5-7.)
Angiotensin II is a potent dipsogen when injected directly into the brain or administered systemically. The major receptors for the dipsogenic action of circulating angiotensin II are located in the subfornical organ. Angiotensin II also stimulates vasopressin secretion, particularly in association with raised plasma osmolality. As such, the renin-angiotensin system may have an important part to play in the control of water balance, particularly during hypovolemia.
Production of angiotensin II in the brain has been implicated in several models of hypertension. Angiotensin also acts on the brain to increase blood pressure, though its effects at this site seem to be less potent than those exerted directly in the systemic circulation. In most animals, the receptors are located in the area postrema. Other central actions of angiotensin II include stimulation of ACTH secretion, suppression of plasma renin activity, and stimulation of Na+ craving, particularly in association with raised mineralocorticoid levels. The full implications of these (and other) central actions of angiotensin remain to be elucidated.
Local Renin-Angiotensin Systems
In addition to the circulating renin-angiotensin system, there is an increasing appreciation that all of the components of the renin-angiotensin system may be present in various tissues and function thereby to promote local production of angiotensin II. Such tissues include the kidney, brain, heart, ovary, adrenal, testis, and peripheral blood vessels. In the kidney, for example, local generation of angiotensin II directly stimulates Na+ reabsorption in the early proximal tubule, in part by activation of the Na+-H+ antiporter in the luminal membrane. Angiotensin II of either local or systemic origin is also of critical importance in the maintenance of GFR during hypovolemia and reduced renal arterial flow. Angiotensin II appears to induce a relatively greater increase in efferent arteriole vasoconstriction, resulting in an increase in hydraulic pressure in the glomerular capillary. This increased pressure protects against a fall in GFR during a reduction in renal perfusion.
THE RENIN-ANGIOTENSIN SYSTEM & HYPERTENSION
Blood pressure is the product of cardiac output and peripheral vascular resistance. The hemodynamic abnormality that appears to underlie essential hypertension is an elevation in peripheral vascular resistance. The determinants of peripheral vascular resistance include a complex array of systemic and locally produced hormones and growth factors as well as neurogenic factors. However, the specific factor or factors that underlie the pathogenesis of essential hypertension remain to be determined. Since the original observation that impaired renal perfusion leads to secretion of renin and an increase in blood pressure, the renin-angiotensin system has been implicated in the etiology of essential hypertension.
In the early 1970s, Laragh and his colleagues suggested that plasma renin activity could be used to categorize the relative contributions of vasoconstriction and intravascular volume expansion in patients with essential hypertension. This so-called“renin profiling” divided patients with essential hypertensive into two subgroups: those with high renin levels, who were said to have a vasoconstrictor mechanism; and those with low renin levels, who were said to have a volume-expanded mechanism. While this bipolar model of hypertension is intellectually attractive, it has not generally been supported by hemodynamic measurements, and for that reason renin profiling of patients with essential hypertension is not generally advocated as part of routine practice.
As noted earlier, dietary Na+ restriction enhances the adrenal but reduces the vascular response to angiotensin II; Na+ loading produces the opposite effect. Thus, for normal subjects ingesting a high-Na+ diet, the Na+-induced modulation of adrenal and vascular activities increases renal blood flow while attenuating renal reabsorption of Na+; both events facilitate excretion of the Na+ load. It has been observed that about one-half of patients with essential hypertension with normal or high plasma renin levels may not modulate their adrenal and vascular responsiveness to a Na+ load. These so-called “nonmodulators” do not increase their renal blood flow in response to a high-salt diet or increase aldosterone secretion in response to a low-salt diet. Thus, according to this model, these patients have an impaired ability to excrete a Na+ load, leading to elevations in blood pressure. The proponents of this hypothesis suggest that there is an abnormality related either to local angiotensin II production or the angiotensin receptor such that target tissue responsiveness is not modified when Na+ intake is altered. Adrenal
and vascular responsiveness can be restored in these patients by reducing angiotensin II levels using ACE inhibitors.
Approximately 25% of patients with essential hypertension have low plasma renin levels. There is an increased frequency in blacks and the elderly, and it has been suggested that the increases in blood pressure in this population are more likely to be salt-sensitive and that the greatest antihypertensive response may be achieved with a diuretic or calcium channel blocker. Although it was initially suggested that ACE inhibitors would not be effective in this low-renin hypertensive population, recent studies suggest that plasma renin levels are not predictive of efficacy of this class of drugs. Conceivably, ACE inhibitors may be effective in this population by increasing levels of bradykinin or by reducing local angiotensin II generation in the kidney, brain, and vasculature. This notion is supported by recent experimental studies in transgenic rats harboring a mouse renin gene. These rats experience a severe and lethal form of hypertension that can be ameliorated by treatment with an ACE inhibitor or angiotensin II receptor antagonist. Although plasma renin activity, plasma angiotensin II levels and renal vein renin content are subnormal, adrenal renin content and plasma prorenin levels are increased in this model, and adrenalectomy attenuates the hypertension. This lends further support to the concept that measurements of systemic renin activity may not reflect the relative importance of local renin-angiotensin systems and their potential role in the pathogenesis of hypertension.
Recent studies using techniques of molecular genetics have further implicated the renin-angiotensin system in the pathogenesis of essential hypertension. A genetic linkage has been described between an allele of the angiotensinogen gene and essential hypertension in affected siblings. It is interesting to note that there is a correlation between plasma concentration of angiotensinogen and blood pressure and that increased levels of angiotensinogen are observed in patients with essential hypertension. Furthermore, normotensive offspring of hypertensive patients tend to have higher levels of angiotensinogen compared with normal control subjects.
The most common cause of renin-dependent hypertension is renovascular hypertension. Various studies have reported it to be present in 1–4% of patients with hypertension, and it is the most common correctable cause of secondary hypertension. Both renovascular disease, defined as the presence of lesions in the renal artery, and renovascular hypertension, defined as renovascular disease that is causal of hypertension, are less common in African-Americans. Renovascular hypertension is usually due either to atherosclerosis or to fibromuscular hyperplasia of the renal arteries. These lesions result in decreased perfusion in the renal segment distal to the obstructed vessel, resulting in increased renin release and angiotensin II production. Blood pressure increase and high angiotensin II levels suppress renin release from the contralateral kidney. Consequently, total plasma renin activity may be only slightly elevated or even normal. Other anatomic lesions may cause hypertension as well: renal infarction, solitary cysts, hydronephrosis, and other parenchymal lesions.
Because of the relatively low incidence of the disorder, screening all hypertensives for renovascular hypertension is generally not recommended. Instead, most physicians look for indications that the hypertension may not be idiopathic before deciding to evaluate the patient for renovascular hypertension. The following clinical conditions are settings in which renovascular hypertension should be suspected: (1) severe hypertension (diastolic blood pressure greater than 120 mm Hg) with either progressive renal insufficiency or refractoriness to aggressive medical therapy; (2) accelerated or malignant hypertension with grade III or grade IV retinopathy; (3) moderate to severe hypertension in a patient with diffuse atherosclerosis or an incidentally detected asymmetry of kidney size; (4) an acute elevation in plasma creatinine concentration in a hypertensive patient that is either unexplained or follows therapy with an ACE inhibitor; (5) an acute rise in blood pressure over a previously stable baseline; (6) a systolic-diastolic abdominal bruit; (7) onset of hypertension below age 20 or above age 50; (8) moderate to severe hypertension in patients with recurrent acute pulmonary edema; (9) hypokalemia with normal or elevated plasma renin levels in the absence of diuretic therapy; and (10) a negative family history of hypertension. An acute deterioration in renal function following therapy with an ACE inhibitor or an ARB should suggest the possibility of bilateral renal artery stenosis. In that situation, both kidneys are dependent on angiotensin II to maintain intraglomerular pressure by its vasoconstrictor effect on the efferent arteriole; loss of this angiotensin II-mediated vasoconstriction will result in a decrease in intraglomerular pressure and GFR.
The standard test for diagnosing renal vascular disease is renal arteriography. Because of risks such as contrast-induced acute tubular necrosis, attempts have made to use newer noninvasive imaging tests and pharmacologic probes as screening tests for renovascular disease. Current noninvasive screening tests for renovascular disease include (1) captopril stimulation with measurement of plasma renin activity; (2) captopril renography; (3) Doppler ultrasound; (4) magnetic resonance angiography; and (5) spiral CT scan.
Basal plasma renin levels by themselves do not serve to diagnose renovascular hypertension inasmuch as levels are increased in only 50–80% of affected patients. The administration of the ACE inhibitor captopril normally induces a reactive hyperreninemia by preventing the negative feedback exerted by angiotensin II. This response is exaggerated in patients with renal artery stenosis such that renin levels measured 1 hour after the oral administration of captopril are much greater than those observed in patients with essential hypertension. The sensitivity and specificity of this test has been reported to range from 93% to 100% and from 80% to 95%, respectively. The test has less sensitivity in blacks, in the young, and in patients with reduced renal function as well as in the presence of concomitant antihypertensive therapy.
Normally, stenosis of a renal artery stimulates the renin-angiotensin system of the ipsilateral kidney such that angiotensin II-mediated vasoconstriction of the efferent arteriole helps maintain intraglomerular pressure and filtration. Administration of an ACE inhibitor (eg, captopril) will result in a reduction in angiotensin II production and thus lower intraglomerular pressure and GFR. Performance of a renal isotope scan prior to and after the administration of captopril scan can optimize detection of unilateral renal ischemia. If there is a relative decrease in isotope uptake in one kidney compared with the other or a delay in peak uptake of isotope, renovascular disease should be suspected. The sensitivity of an ACE inhibitor-augmented renal scan for significant renal artery stenosis is about 90% in high-risk patients. However, the sensitivity is reduced in patients with bilateral renal artery stenosis and in low-risk patients.
The combination of direct ultrasound imaging of the renal arteries (B-mode imaging) and measurement of renal arterial flow by Doppler technique has recently been become a popular screening test for renal artery stenosis. Studies suggest that the positive and negative predictive values for these procedures are in the upper 90% range. Having an experienced operator is important to achieve this level of performance. Visualization of the renal arteries can be impaired by the presence of a large amount of bowel gas, obesity, recent surgery, or the presence of an accessory renal artery.
Magnetic resonance angiography (MRA) has recently been advocated as a good screening test for renal artery stenosis. Initial sensitivities have been reported in the 92–97% range. A recent study suggests that spiral CT scan may be the most sensitive noninvasive imaging test to evaluate for renal artery stenosis, with sensitivity and specificity of 98% and 94%, respectively. These results are promising, and more studies are needed to clarify the utility of these imaging tests for renal vascular disease.
Given that there is no noninvasive imaging test that is sensitive enough to totally exclude renal artery stenosis, clinicians are frequently confronted with the dilemma of when and how a patient with hypertension should be evaluated for renovascular hypertension. Based on the index of clinical suspicion (Table 10-1), Mann and Pickering have developed a practical algorithm for the evaluation of renovascular hypertension and for the selection of patients for renal arteriography (Figure 10-11).
Table 10-1. Testing for renovascular hypertension: Clinical index of suspicion as a guide to workup.1
Figure 10-11. Suggested workup for renovascular hypertension. (Reproduced, with permission, from Mann SJ, Pickering TG: Detection of renovascular hypertension. State of the art: 1992. Ann Intern Med 1992;117:845.)
Anatomic correction is the preferred therapy for renovascular hypertension when it is possible and the patient is considered able to tolerate the procedure. The arteriographic finding of a greater than 75% stenosis in either or both renal arteries suggests that the patient may have physiologically significant renal artery stenosis. Prior to correction of a stenotic renal artery, it had been suggested that measurements of renal vein renins be performed to determine whether the stenosis is hemodynamically significant. In selective venous sampling, blood samples are obtained from the venous effluent of the affected portion of the kidney and from the contralateral kidney. The renin level is ordinarily significantly higher in the sample from the affected kidney than in that from the contralateral kidney. When the value for the affected kidney sample is divided by the value for the unaffected sample, a ratio greater than 1.5 generally indicates a functional abnormality, though a lower ratio does not exclude the diagnosis. Giving an ACE inhibitor prior to the renal vein sampling may increase the sensitivity of this test. Over 90% of patients with renal artery stenosis and lateralizing renal vein renins will have an improvement in blood pressure control following therapy. However, since many patients with renal vein renin ratios less than 1.5 (nonlateralizing) will have an amelioration of their hypertension after angioplasty or surgery, it is no longer routine to perform such studies in patients with a high-grade renal artery stenosis. Measurement of renal vein renin levels may be helpful in evaluating hypertensive patients with bilateral or segmental renal artery stenosis in order to determine which kidney or region of a kidney is the source of the augmented renin release. A recent study suggests that calculating the resistance index ([1 – end-diastolic velocity divided by maximal systolic velocity] × 100) using duplex Doppler ultrasonography may be helpful in predicting the success rates of revascularization procedures for the treatment of renovascular hypertension. Patients with resistance indices > 80 generally had a poor surgical outcome, with renal function decreasing in about 80% of the patients, and only one patient had a significant decline in blood pressure. In contrast, over 90% of patients with a resistance index < 80 had an improvement in blood pressure control after revascularization procedures. An elevated resistance index is probably indicative of intrarenal vascular disease and possible glomerulosclerosis, and revascularization of the main renal arteries thus may not improve blood pressure control and renal function.
Anatomic correction can be performed either with percutaneous angioplasty (with or without stent placement) or with surgical intervention. The best method of treating patients with renovascular hypertension remains a matter of speculation since there have been no truly randomized trials that have compared angioplasty with or without stent versus surgery versus medical therapy. Angioplasty is the procedure of choice for renovascular hypertension due to fibromuscular dysplasia, with cure rates between 50% and 85%, improvement in 30–35%, and failure rates less than 15%. For atherosclerotic renal artery stenosis, the optimal treatment regimen is much less clear. The technical success rates vary with the site of the lesion. In general, lesions within the main renal artery are most amenable to angioplasty, whereas ostial lesions do not respond as well to angioplasty and require stent placement. Using angioplasty alone for the treatment of atherosclerotic renal artery disease results in cure rates for hypertension between 8% and 20%, improvement in 50–60%, and failure rates between 20% and 30%. In addition, with angioplasty alone, there is an 8–30% restenosis rate at 2 years. Patients with bilateral renal artery disease or chronic hypertension have even less impressive improvement in hypertension with angioplasty alone. Recently, the placement of stents in the renal arteries has been used to improve the efficacy of angioplasty. Cure or improvement in hypertension has been reported in 65–88% of patients, with restenosis rates of only 11–14% in a number of uncontrolled studies. Another major issue in the treatment of renovascular disease is to determine which patients would benefit from procedures designed to preserve or improve renal function,
especially if the patient has bilateral renal artery stenosis that results in reduced renal blood flow and glomerular filtration. A discussion of this interesting issue is beyond the scope of this chapter.
Surgical correction of renal artery stenosis usually involves endarterectomy or a bypass procedure. Although surgical correction is generally more effective than angioplasty in curing hypertension, operative mortality can be much greater, especially in older patients with concomitant cardiovascular and cerebrovascular disease. In most medical centers, the current revascularization procedure of choice is percutaneous angioplasty with stent implantation, especially in patients with ostial or proximal lesions. Surgical revascularization is considered if angioplasty fails or if the patient requires concomitant aortic surgery.
Renovascular hypertension can also be treated medically; this treatment is used when the patient is considered unable to tolerate a surgical procedure or the diagnosis is uncertain. In fact, recent randomized controlled trials in patients with renovascular hypertension have suggested that there may not be a clear benefit of revascularization over conservative medical therapy. The ACE inhibitors and selective AT1 antagonists are particularly effective, although they can lower intrarenal efferent arteriolar resistance and so decrease renal function in patients with bilateral renal artery stenosis. Renovascular hypertension may also respond to beta-adrenergic antagonists and calcium channel blockers.
Renin-secreting tumors are extremely rare. The tumors are usually hemangiopericytomas containing elements of the juxtaglomerular cells. They can be located by CT scan and the presence confirmed by measurement of renin in the venous effluent. Other renin-secreting neoplasms (eg, Wilms' tumor) have been reported, including a pulmonary tumor that secreted excessive amounts of renin, producing hypertension and hypokalemia with secondary aldosteronism.
Accelerated hypertension is characterized by marked elevations of diastolic blood pressure that can be abrupt in onset. This disorder is associated with progressive arteriosclerosis. The plasma levels of renin and aldosterone may be extremely high. It is believed that the intense vasospastic events that occur and the excessive renal cortical nephrosclerosis lead to hyperreninemia and accelerate the hypertensive process. Vigorous antihypertensive therapy usually will result in a reduction in the vasospastic process and an amelioration of hyperreninemia with time.
Aldosterone levels may be increased during treatment with replacement estrogen therapy or oral contraceptives. This is due to an increase in angiotensinogen production and presumed increase in angiotensin II levels. Aldosterone levels increase secondarily, but hypokalemia rarely occurs during estrogen administration.
OTHER HORMONE SYSTEMS & HYPERTENSION
Hyperinsulinemia and insulin resistance have been implicated as potential factors in the generation of hypertension, particularly in obese patients. It has been argued that insulin resistance is present in most obese patients with hypertension and in some nonobese hypertensive patients. In the setting of obesity, there is impaired insulin-mediated glucose uptake resulting in both type 2 diabetes mellitus and increased insulin secretion by the pancreas (hyperinsulinemia). The distribution of body fat may also be a key factor, inasmuch as hypertension and insulin resistance are seen more commonly in patients with abdominal obesity (upper body, male-type fat distribution). The association of hypertension, diabetes mellitus, abdominal obesity, and hyperlipidemia has been referred to as “syndrome X” or the syndrome of insulin resistance.
The hypertension observed in this clinical syndrome may be due in part to the hyperinsulinemia. Insulin accentuates the activity of the sympathetic nervous system, leading to greater vasoconstriction. In addition, insulin increases Na+ reabsorption by the kidney, resulting in increased intravascular volume and blood pressure. Although insulin usually induces vasodilation to counterbalance these pressor forces, in the setting of obesity this action is attenuated. Thus, in these insulin-resistant states, it is postulated that the stimulation of both the sympathetic nervous system and renal Na+ reabsorption by hyperinsulinemia combined with impaired vasodilation results in increased blood pressure. It is noteworthy that weight loss lowers both blood pressure, insulin levels, and insulin resistance in these patients.
Increased insulin levels alone are probably not sufficient to cause hypertension given the observations that experimental animals receiving high doses of insulin and patients with insulinomas do not develop hypertension. In addition, there are a substantial number of patients with obesity, insulin resistance, and type 2 diabetes mellitus who do not have hypertension (eg, Pima Indians). Thus, there is probably a critical interplay of genetic and
hormonal factors in the pathogenesis of hypertension in patients with insulin resistance. (See Chapter 18.)
Extracts of atrial but not ventricular tissue cause marked natriuresis when injected into rats. The material is contained in densely staining granules in the atria of most mammalian species. Atrial natriuretic peptide (ANP) is a 28-amino-acid peptide derived from cleavage of the carboxyl terminal of a 126-amino-acid precursor located primarily in the storage vesicles of atrial cells. At least three other natriuretic peptides have subsequently been identified: a brain natriuretic peptide (BNP; 32-amino acids), C-type peptide (CNP; 22-amino acids), and a renal natriuretic peptide (urodilatin; 32-amino acids). Although originally described in the brain, the major source of BNP is the cardiac ventricle, and its action is similar to that of ANP. CNP is mainly produced in the brain, where it serves as a neurotransmitter and in endothelial cells, where it may regulate vasoconstriction. Urodilatin is produced in the kidney, where it acts locally to affect Na+ transport.
These natriuretic peptides bind to membrane receptors linked to guanylyl cyclase, resulting in production of the second messenger, cGMP. The major effects seen following the administration of ANP are vasodilation, hyperfiltration, and natriuresis. Although the peptide can cause relaxation of vascular smooth muscle, the fall in blood pressure is thought to be due largely to reduction of venous return and depression of cardiac output in intact animals. In the kidney, ANP increases GFR probably by inducing a relative afferent arteriolar dilation and efferent arteriolar vasoconstriction and an increase in glomerular permeability. The natriuresis is due both to the increase in GFR and to the direct inhibition by ANP of Na+ and water reabsorption by inner medullary and cortical collecting duct cells. ANP inhibits secretion of renin, aldosterone, vasopressin, and ACTH as well as the stimulation of heart rate mediated by the baroreceptors.
Maneuvers that expand plasma volume and increase atrial pressure are associated with increased levels of ANP in plasma. Thus, when blood volume increases, the associated increase in atrial pressure and atrial stretch may trigger secretion of the peptide and lead to natriuresis and blood pressure reduction. However, the precise role ANP plays in the control of Na+ balance, blood volume, and blood pressure regulation under normal physiologic conditions is not clear, and there are no known roles for impaired ANP secretion in the pathogenesis or maintenance of essential hypertension. Because of the pharmacologic effects of the natriuretic peptides to induce vasodilation, hyperfiltration, and natriuresis, studies are under way to determine if these peptides may have a therapeutic role in the treatment of hypertension, heart failure, and renal failure. Whether ANP will be a useful therapy for congestive heart failure is uncertain inasmuch as patients with chronically increased atrial pressures already have increased plasma levels of the peptide.
ENDOTHELIUM-DERIVED RELAXING FACTOR
The vascular endothelium produces a labile substance, endothelium-derived relaxing factor (EDRF), that mediates the vasorelaxant actions of various endogenous hormones including acetylcholine. EDRF has been identified as nitric oxide, which is synthesized from the guanidine nitrogen atom of the amino acid L-arginine by the enzyme nitric oxide synthase. Nitric oxide diffuses within the cell or to adjacent cells such as smooth muscle cells, where it stimulates soluble guanylyl cyclase. The resultant increase in cyclic guanosine monophosphate leads to a relaxation of vascular smooth muscle cells and therefore vasodilation (see Chapter 3). A number of recent studies in laboratory animals and human subjects have shown that nitric oxide synthesized by the vascular endothelium is an important determinant of resting peripheral vascular resistance and blood pressure. In anesthetized rabbits, inhibition of the activity of nitric oxide synthase using substituted arginine analogs (L-monomethyl arginine) acutely increased blood pressure. This hypertensive effect can be reversed by the infusion of arginine. In normal subjects, infusion of L-arginine decreases peripheral vascular resistance, causing hypotension and a reflex tachycardia. Because of this apparently important role of nitric oxide in maintaining basal blood pressure, it has been proposed that the nitric oxide pathway may be abnormal in patients with hypertension. This view has been supported by recent studies in humans. For example, patients with essential hypertension have a diminished vasoconstrictor response to an infusion of arginine analogs and a reduced arterial vasodilatory response to acetylcholine, suggesting that both the basal and stimulated release of nitric oxide is reduced in this disease. In contrast, the response to the endothelium-independent vasodilator nitroprusside was normal in patients with essential hypertension, suggesting that abnormality is a result of reduced nitric oxide production by the endothelium rather than impaired response in the vascular smooth muscle. The mechanisms responsible for this endothelial dysfunction are not known.
In addition to the production of the potent vasodilator, nitric oxide, the vascular endothelium produces a potent
vasoconstrictor peptide, endothelin. At least three endothelin peptides have been identified: endothelin-1, endothelin-2, and endothelin-3. The predominant vascular vasoconstrictor, endothelin-1, is formed from proendothelin-1 by the action of a metalloprotease, endothelin-converting enzyme. Endothelin-1 binds to receptors in vascular smooth muscle which are linked to phospholipase C, resulting in the hydrolysis of phosphoinositide to inositol triphosphate.
Increased endothelin activity has been observed in disorders associated with vasoconstriction such as malignant hypertension, heart failure, pulmonary hypertension, contrast-induced acute tubular necrosis, and myocardial infarction. A rare tumor, hemangioendothelioma, can cause hypertension by the secretion of large quantities of endothelin. In addition, the hypertension associated with the use of cyclosporine may be due to increased endothelin production. However, a conclusive role for endothelin in the pathogenesis of essential hypertension has not been demonstrated.
Kinins are potent vasodilators formed in blood vessels. They are cleaved from the precursor kininogen by the enzymatic action of kallikrein. Kallikrein activity has been noted to be reduced in patients with essential hypertension, suggesting lower vasodilatory kinin production. ACE is known to inactivate bradykinin, leading to the suggestion that the hypotensive effect of ACE inhibitors may be due, in part, to increased bradykinin levels. Moreover, the improved insulin sensitivity and glucose utilization observed in diabetic patients treated with ACE inhibitors may be the result of increased kinin levels rather than reduced angiotensin II production.
OTHER HORMONES & AUTACOIDS
Prostaglandins, vasopressin, calcitonin gene-related peptide, parathyroid hormone, and parathyroid hormone-related peptide are vasoactive hormones or autacoids that have been implicated in the regulation of blood pressure. Although vasopressin is both a potent vasoconstrictor and a prime factor in water reabsorption by the kidney, it does not appear to be a factor in the pathogenesis of essential hypertension. Calcitonin gene-related peptide is a potent vasodilator produced in the central nervous system and in autonomic nerves innervating blood vessels. It has been suggested that calcitonin gene-related peptide may mediate the hypotensive effect of calcium supplements given to hypertensive patients. Both infusions of parathyroid hormone and parathyroid hormone-related peptide can produce hypotension. Thus, the hypertension commonly seen in primary hyperparathyroidism is probably due to other factors.
SYMPATHETIC NERVOUS SYSTEM
Increased activity of the sympathetic nervous system has been implicated as a contributing factor in the pathogenesis of essential hypertension. This may be due to both genetic and environmental factors. Some patients with hypertension, particularly during the early stages, as well as normotensive offspring of hypertensive patients have enhanced sympathetic nervous system activity. It has been postulated that impaired baroreceptor function may prevent the normal inhibitory check on increases in sympathetic activity. In addition, the role of stress in the generation and maintenance of hypertension probably is mediated, in part, by activation of the sympathetic nervous system. The mechanisms by which increased sympathetic nervous system activity and catecholamines increase blood pressure is multifactorial, including augmented vasoconstriction, increased cardiac output, increased activity of the renin-angiotensin system, and enhanced Na+ reabsorption by the kidney. Disorders of catecholamine metabolism are discussed in further detail in Chapter 11.
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