The body regulates Na+ excretion by three major mechanisms:
1. Changes in renal hemodynamics alter the Na+ load presented to the kidney and regulate Na+ reabsorption in the proximal tubule and distal nephron. We discuss these hemodynamic effects in the next four sections.
2. Three factors that respond to decreases in “effective circulating volume”—the renin-angiotensin-aldosterone axis, renal sympathetic nerve activity, and AVP (see pp. 554–555)—do so in part by increasing Na+reabsorption in various nephron segments. We discuss these factors in the fifth section.
3. Several factors that respond to increases in effective circulating volume—including atrial natriuretic peptide and dopamine—do so in part by reducing Na+ reabsorption in various segments of the nephron. That is, they produce a natriuresis. We discuss these factors in the final section of this chapter.
Glomerulotubular balance stabilizes fractional Na+ reabsorption by the proximal tubule in the face of changes in the filtered Na+ load
When hemodynamic changes (e.g., caused by a high-protein diet, intense exercise, severe pain, or anesthesia) alter GFR and thus the Na+ load presented to the nephron, proximal tubules respond by reabsorbing a relatively constant fraction of the Na+ load. This constancy of fractional Na+ reabsorption along the proximal tubule—glomerulotubular (GT) balance—is independent of external neural and hormonal control, and prevents spontaneous fluctuations in GFR from causing marked changes in Na+ excretion.
Figure 35-10 shows how the absolute reabsorption of Na+ increases proportionally with increases in the filtered Na+ load, achieved by varying GFRs at constant plasma [Na+]. The amount of luminal Na+remaining at the end of the proximal tubule also increases linearly with the filtered Na+ load. However, fractional reabsorption of Na+ and water in the proximal tubule is not always constant—that is, proximal GT balance is not always perfect—as we will see below. Moreover, at the level of the whole kidney, GT balance is not perfect, mainly because distal-nephron Na+ absorption is under neural and hormonal control (see p. 765).
FIGURE 35-10 Constancy of fractional Na+ reabsorption by the proximal tubule.
The proximal tubule achieves GT balance by both peritubular and luminal mechanisms
How do the proximal-tubule cells sense that the GFR has changed? Both peritubular and luminal control mechanisms contribute, although no agreement exists concerning their relative roles.
Peritubular Factors in the Proximal Tubule
As discussed in Chapter 34, Starling forces across the peritubular capillary walls determine the uptake of interstitial fluid and thus the net reabsorption of NaCl and fluid from the tubule lumen into the peritubular capillaries (see pp. 747–749). These peritubular physical factors also play a role in GT balance. We can distinguish a sequence of three transport steps as reabsorbed fluid moves from the tubule lumen into the blood (Fig. 35-11A):
Step 1: Solutes and water enter a tubule cell across the apical membrane.
Step 2: Solutes and water from step 1 (i.e., “reabsorbate”) exit the tubule cell across the basolateral membrane and enter an intercellular compartment—the lateral interspace—that is bounded by the apical tight junction, the basolateral tubule-cell membranes, and a basement membrane that does not discriminate between solutes and solvent. Steps 1 and 2 constitute the transcellular pathway.
Step 3: The reabsorbate can either backleak into the lumen (step 3a) or move sequentially into the interstitial space and then into the blood (step 3b).
FIGURE 35-11 Peritubular mechanisms of GT balance. In A, PPC and πPC are, respectively, the hydrostatic and the oncotic pressures in the peritubular capillaries. At the level of the tubule, the net Na+ reabsorption is the difference between active transcellular transport and passive backleak through the paracellular pathway. At the level of the peritubular capillary, net fluid absorption is the difference between fluid absorption (driven by πPC) and fluid filtration (driven by PPC). In B, increasing the filtered fraction has effects on both the tubule and the peritubular capillaries. At the level of the tubule, the increased concentrations of Na+-coupled solutes (e.g., glucose) increase active transport. At the level of the capillaries, the lower PPC and higher protein concentration (πPC) pull more fluid from the interstitium. The net effect is reduced passive backleak.
At normal GFR (see Fig. 35-11A), reabsorptive Starling forces—the low hydrostatic and high oncotic pressure in the capillaries—cause an extensive uptake of reabsorbate into the capillaries.
Because of GT balance, spontaneous alterations in GFR lead to changes in peritubular pressures (both hydrostatic and oncotic) that, in turn, modulate the forces that govern step 3. Peritubular mechanisms of GT balance come into play only when the changes in GFR are associated with alterations in filtration fraction (FF = GFR/[renal plasma flow]; see p. 746). Consider an example in which we increase GFR at constant glomerular plasma flow, thereby increasing FF (see Fig. 35-11B). We can produce this effect by increasing efferent arteriolar resistance while concomitantly decreasing afferent arteriolar resistance (see Fig. 34-8A, bottom section). The result is an increase in glomerular capillary pressure (i.e., net filtration pressure) without a change in overall arteriolar resistance. These changes have two important consequences for peritubular capillaries. First, the increased GFR translates into less fluid remaining in the efferent arteriole, so that peritubular oncotic pressure (πPC) rises. Second, the increased GFR also translates to slightly less blood flowing into the efferent arteriole, which slightly decreases hydrostatic pressure in the peritubular capillaries (PPC). As a consequence, the net driving force increases for the transport of fluid from the lateral interspace into the capillaries; this results in a more effective absorption of fluid and NaCl. The opposite sequence of events occurs with a spontaneous fall in GFR, which leads to a decrease in FF. The response is a decrease in the net reabsorption of Na+ and water by the proximal tubule that tends to maintain constancy of fractional Na+ reabsorption and GT balance.
Luminal Factors in the Proximal Tubule
Luminal factors also contribute to GT balance, as evidenced by the observation that increased flow along the proximal tubule—without any peritubular effects—leads to an increase in fluid and NaCl reabsorption. The luminal concentrations of solutes such as glucose, amino acids, and fall along the length of the proximal tubule as the tubule reabsorbs these solutes (see Fig. 35-6). Increasing luminal flow would, for instance, cause luminal [glucose] to fall less steeply along the tubule length, and more glucose would be available for reabsorption at distal sites along the proximal tubule. The net effect is that, integrated over the entire proximal tubule, higher luminal flows increase the reabsorption of Na+, glucose, and other Na+-coupled solutes.
A second luminal mechanism may revolve around flow sensing. Increased flow may cause increased bending of the central cilium or the microvilli on the apical membrane, which may signal increased fluid reabsorption. Third, humoral factors in the glomerular filtrate may also contribute to GT balance. If one harvests tubule fluid and injects it into a single proximal tubule, Na+ reabsorption increases. Angiotensin II (ANG II)—a small peptide hormone that is both filtered in the glomeruli and secreted by proximal-tubule cells—increases Na+ reabsorption in the proximal tubule.
ECF volume contraction or expansion upsets GT balance
As noted above, proximal GT balance is not always perfect. For instance, if excessive Na+ loss (e.g., sweating or diarrhea) contracts the ECF volume—thereby reducing renal perfusion pressure, GFR, and the filtered Na+ load—perfect GT balance would reduce renal Na+ and water excretion. In fact, in volume contraction, the fractional reabsorption of Na+ and water increases in the proximal tubule, so that renal Na+and water excretion fall beyond that expected for perfect GT balance. Conversely, if ingestion or administration of a high Na+ load expands ECF, fractional reabsorption of Na+ and water in the proximal tubule falls, which enhances renal Na+ excretion beyond that expected for perfect GT balance. These effects result, in part, from the same hemodynamic factors maintaining GT balance, as well as from direct regulation of transcellular Na+ reabsorption in the proximal tubule.
During ECF and plasma volume contraction, blood pressure and renal blood flow will tend to fall. Under these conditions, prostaglandins mediate afferent arteriolar dilation (see p. 753) and ANG II mediates efferent arteriolar constriction (see p. 752), thereby preventing GFR from falling in proportion to the reduction in renal blood flow. Thus, FF will increase. The resulting increase in peritubular protein concentration will raise peritubular oncotic pressure (πPC), reducing backleak of reabsorbate and thereby enhancing net tubule reabsorption of Na+ salts and water. In addition, ANG II—levels of which increase during volume contraction—binds to AT1 receptors on proximal-tubule cells, which results in stimulation of transcellular Na+ reabsorption. The converse series of events will take place during volume expansion.
The distal nephron also increases Na+ reabsorption in response to an increased Na+ load
The tubules of the distal nephron, like their proximal counterparts, also increase their absolute magnitude of Na+ reabsorption in response to increased flow and Na+ delivery. The principle is the same as that for glucose transport in the proximal tubule, except here it is luminal [Na+] that falls less steeply when flow increases (Fig. 35-12A). Because the transport mechanisms responsible for Na+ reabsorption by the distal nephron are more effective at higher luminal [Na+] values, reabsorption at any site increases with flow (see Fig. 35-12B). In contrast to GT balance in the proximal tubule, increasing flow by a factor of 4 in the distal nephron may cause cumulative Na+ reabsorption to rise by only a factor of 2 (see Fig. 35-12C).
FIGURE 35-12 Flow dependence of Na+ transport in the distal nephron. A and B are idealized representations of the effect of increased flow () on luminal [Na+] and Na+ reabsorption rate (JNa) along the TAL. Limiting [Na] is the theoretical minimal value that the tubule could achieve at zero flow. C summarizes the effect of flow on cumulative Na+ reabsorption.
The load dependence of Na+ reabsorption in the TAL is of clinical importance because it explains why diuretic agents acting on the proximal tubule are relatively less effective in enhancing Na+ excretion than one would expect from the large fraction of filtered Na+ that the proximal tubule reabsorbs. Thus, although carbonic anhydrase inhibitors are potent blockers of proximal Na+ and water reabsorption, the increased delivery of Na+ to the TAL and distal nephron results in a large increase in Na+ reabsorption in these segments, greatly reducing the ultimate loss of Na+ in the final urine.
Four parallel pathways that regulate effective circulating volume all modulate Na+ reabsorption
GT balance is only one element in a larger, complex system for controlling Na+ balance. As we see in Chapter 40, the control of effective circulating volume (i.e., Na+ content) is under the powerful control of four parallel effectors (see pp. 554–555): the renin-angiotensin-aldosterone axis, the sympathetic nervous system, AVP, and atrial natriuretic peptide (ANP). In Chapter 34 we saw how these factors modulate renal blood flow and GFR (see pp. 752–753). Here, we briefly discuss how these four effectors modulate Na+ reabsorption, a subject that we will treat more comprehensively beginning on page 836.
ANG II—the second element in the renin-angiotensin-aldosterone axis (see pp. 841–842)—binds to AT1 receptors at the apical and basolateral membranes of proximal-tubule cells and, predominantly via protein kinase C, stimulates NHE3. ANG II also upregulates expression of NHE3 and NKCC2 in the TAL. Moreover, ANG II upregulates NCC activity in the DCT and stimulates apical Na+ channels in the ICT. These effects promote Na+ reabsorption. Complex interactions among intracellular kinases (e.g., WNK4 and SPAK) mediate the effects of ANG II on the DCT and ICT.
Aldosterone—the final element in the renin-angiotensin-aldosterone axis—stimulates Na+ reabsorption by NCC in the DCT and by the ENaC in the late DCT, connecting tubule, and collecting ducts. Normally, <10% of the filtered Na+ load is under humoral control by aldosterone. Nevertheless, the sustained loss of even a small fraction of the filtered Na+ load would exceed the daily Na+ intake significantly. Accordingly, the lack of aldosterone that occurs in adrenal insufficiency (Addison disease) can lead to severe Na+ depletion, contraction of the ECF volume, low plasma volume, and hypotension. N35-2
Acute Effects of Intravenous Aldosterone
Contributed by Gerhard Giebisch, Erich Windhager
eFigure 35-1 shows the renal effects of intravenously administered aldosterone. The acute effects include significant decreases in Na+ and Cl− excretion, as well as increases in K+ and excretion. The reverse changes occur in adrenalectomy, and the administration of mineralocorticoids (e.g., aldosterone) promptly reverses these deficiencies.
EFIGURE 35-1 Acute effects of intravenously administered aldosterone on electrolyte excretion in humans. (Data from Liddle GW: Aldosterone antagonists. Arch Intern Med 102:998–1005, 1958.)
Aldosterone acts on its target tissues by binding to cytoplasmic mineralocorticoid receptors (MRs) that then translocate to the nucleus and upregulate transcription (see pp. 71–72), as illustrated for the case of principal cells of the collecting ducts in Figure 35-13A. Thus, the effects of aldosterone require a few hours to manifest themselves because they depend on the increased production of aldosterone-induced proteins. The ultimate cellular actions of aldosterone include upregulation of apical ENaCs, apical K+ channels, the basolateral Na-K pump, and mitochondrial metabolism. The effects on ENaC involve an increase in the product of channel number in the apical membrane and open probability (NPo), and thus apical Na+ permeability. The simultaneous activation of apical Na+ entry and basolateral Na+ extrusion ensures that, even with very high levels of Na+ reabsorption, [Na+]i and cell volume are stable. Long-term exposure to aldosterone leads to the targeting of newly synthesized Na-K pumps to the basolateral membrane and to amplification of the basolateral membrane area.
FIGURE 35-13 Cellular actions of aldosterone. The inset in A shows the upregulation of ENaC Na+ channels, based on patch-clamp data from the rat CCT. N is the number of channels in the patch and PO is the open probability. For simplicity, the blowup in B shows only the α subunit of the trimeric ENaC, which also has β and γ subunits. SGK1 not only phosphorylates Nedd4-2 but also Ser-621 of the α subunit (which is important for the rapid activation of the channel). In C, 11β-HSD2 prevents cortisol (a glucocorticoid), which is present at high plasma concentrations, from having mineralocorticoid effects in the target cell. In D, with the enzyme blocked, cortisol acts as a mineralocorticoid. mRNA, messenger RNA.
Aldosterone upregulates serum- and glucocorticoid-induced kinase (SGK), which phosphorylates and thereby inhibits the ubiquitin ligase Nedd4-2 (see Fig. 35-13B). The net effect is reduced ubiquitination—and thus reduced endocytosis of ENaC—and increased apical membrane abundance of ENaC.
Because MRs distinguish poorly between glucocorticoids and mineralocorticoids, and because plasma concentrations of glucocorticoids greatly exceed those of aldosterone, one would expect glucocorticoids to exert a mineralocorticoid effect and cause Na+ retention. Under normal conditions, this does not happen because of the enzyme 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2), N35-3 which colocalizes with intracellular MRs (see Fig. 35-13C). This enzyme irreversibly converts cortisol into cortisone (see p. 1021), an inactive metabolite with low affinity for MRs. In sharp contrast, the enzyme does not metabolize aldosterone. Thus, 11β-HSD2 enhances the apparent specificity of MRs by protecting them from illicit occupancy by cortisol. As may be expected, an 11β-HSD2 deficiency may cause apparent mineralocorticoid excess (AME), with abnormal Na+ retention, hypokalemia, and hypertension. Carbenoxolone, a specific inhibitor of 11β-HSD2, prevents metabolism of cortisol in target cells, thus permitting abnormal activation of MRs by this glucocorticoid. Another inhibitor of 11β-HSD2 is glycyrrhetinic acid, a component of “natural” licorice (see Fig. 35-13D). N35-4 Thus, natural licorice can also cause the symptoms of AME.
Reaction Catalyzed by 11β-Hydroxysteroid Dehydrogenase
Contributed by Eugene Barrett
Refer to Figure 50-2, specifically the cortisol molecule (4-pregnen-11β,17α,21-triol-3,20-dione), which has two highlighted hydroxyl groups—one on the C ring at position 11 and another on the D ring at position 17. The enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD) removes one H from the hydroxyl group at position 11 and another H from the same carbon, yielding a ketone group (O=C) at position 11. The product of this reaction is cortisone (4-pregnen-17α,21-diol-3,11,20-trione). Thus, the enzyme converts a triol (three hydroxyl groups)/dione (two ketone groups) to a diol (two hydroxyl groups)/trione (three ketone groups).
Licorice as a Cause of Apparent Mineralocorticoid Excess
Contributed by Emile Boulpaep, Walter Boron
Glycyrrhizic acid is a chemical that consists of glycyrrhetinic acid (3-β-hydroxy-11-oxoolean-12-en-30-oic acid) conjugated to two glucuronic acid moieties. Glycyrrhizic acid is 150-fold sweeter than sucrose. It is naturally produced by the plant Glycyrrhiza glabra (Leguminosae) and is also present in European licorice. American licorice manufacturers generally substitute anise for glycyrrhizic acid.
Glycyrrhetinic acid and the glycyrrhetinic acid moiety of glycyrrhizic acid have the curious property that they inhibit the enzyme 11β-hydroxysteroid dehydrogenase (11βHSD). This enzyme converts cortisol into cortisone. N35-3 Because cortisol has a much higher affinity for the MR than does the breakdown product cortisone, inhibition of 11βHSD produces the same symptoms as a bona fide excess of mineralocorticoids. As described on page 766, this excess leads to Na+ retention and hypertension.
These compounds also inhibit 15-hydroxyprostaglandin dehydrogenase in the surface cells of the stomach and thereby increase levels of prostaglandins that protect the stomach from acid damage. This same action may also promote the release of mucus in the airway, which is why the active compounds of licorice have been used as expectorants.
True licorice has long been used as an herbal medicine.
Dalton L. What's that stuff? Licorice. Chem Eng News. 2002;80(32):37 http://pubs.acs.org/cen/whatstuff/stuff/8032licorice.html [Accessed October 2015].
Sympathetic Division of the Autonomic Nervous System
Sympathetic nerve terminals in the kidney release norepinephrine, which has two major direct effects on Na+ reabsorption. First, high levels of sympathetic stimulation markedly reduce renal blood flow and, therefore, GFR (see p. 752). A decreased filtered load of Na+ will tend to cause Na+ excretion to fall. Second, even low levels of sympathetic stimulation activate α-adrenergic receptors in proximal tubules. This activation stimulates both the apical NHE3 and basolateral Na-K pump (see Fig. 35-4A), thereby increasing Na+ reabsorption, independent of any hemodynamic effects. Conversely, surgical denervation of the kidneys can reduce blood pressure in patients with resistant hypertension.
Arginine Vasopressin (Antidiuretic Hormone)
Released by the posterior pituitary, AVP binds to a V2 receptor at the basolateral membrane of target cells. Acting via Gs, the AVP increases [cAMP]i (see pp. 56–57). As discussed in Chapter 38, the overall renal effect of AVP in humans is to produce urine with a high osmolality and thereby retain water (see pp. 817–818). However, AVP also stimulates Na+ reabsorption. In the TAL, AVP stimulates the apical NKCC2 and K+ channels (see Fig. 35-4B). In principal cells of the ICT and CCT, AVP stimulates Na+ transport by increasing the number of open Na+ channels (NPo) in the apical membrane. N35-5
Effects of AVP on Na+ Channels
Contributed by Gerhard Giebisch, Erich Windhager
As noted in the text, AVP increases the number of open Na+ channels (NPo) in the initial and cortical collecting tubules. This effect may reflect fusion of Na+ channel–containing vesicles with the apical cell membrane or activation of pre-existing Na+ channels in the membrane by cAMP-dependent protein kinase.
Atrial Natriuretic Peptide
Of the four parallel effectors that control effective circulating volume, ANP (see p. 843) is the only one that promotes natriuresis. A polypeptide released by atrial myocytes (see p. 553), ANP stimulates a receptor guanylyl cyclase to generate cGMP (see p. 66). The major effects of ANP are hemodynamic. N35-6 It causes renal vasodilation by increasing blood flow to both the cortex and the medulla. Increased blood flow to the cortex raises GFR and increases the Na+ load to the proximal tubule and to the TAL (see pp. 752–753). Increased blood flow to the medulla washes out the medullary interstitium (see pp. 813–815), thus decreasing osmolality and ultimately reducing passive Na+ reabsorption in the thin ascending limb (see p. 811). The combined effect of increasing cortical and medullary blood flow is to increase the Na+ load to the distal nephron and thus to increase urinary Na+ excretion. In addition to having hemodynamic effects, ANP directly inhibits Na+ transport in the inner medullary collecting duct, perhaps by decreasing the activity of nonselective cation channels in the apical membrane.
Renal Actions of ANP
Contributed by Gerhard Giebisch, Erich Windhager
eFigure 35-2 summarizes the effects of ANP on targets along the nephron.
Regarding step 13 in the figure, patch-clamp studies show that cGMP directly decreases the activity of nonselective cation channels in the apical membrane of the medullary collecting duct.
EFIGURE 35-2 Sites of action of ANP. UNa, urinary sodium excretion rate. (Data from Atlas SA, Maack T: Atrial natriuretic factor. In Windhager EE (ed): Handbook of Physiology, Section 8: Renal Physiology. New York, Oxford University Press, 1992, pp 1577–1674.)
Dopamine, elevated plasma [Ca2+], an endogenous steroid, prostaglandins, and bradykinin all decrease Na+ reabsorption
Aside from ANP (see previous section), five humoral agents have significant natriuretic action, in part due to inhibition of Na+ reabsorption at the level of the tubule cell.
From circulating L-dopa, proximal-tubule cells use L-amino acid decarboxylase (see Fig. 13-8C) to form dopamine, which they then secrete into the tubule lumen. Na+ loading increases the synthesis and urinary excretion rate of dopamine, whereas a low Na+ diet has the opposite effect. As noted above, dopamine causes renal vasodilation (see p. 753), which increases Na+ excretion. Dopamine also directly inhibits Na+reabsorption at the level of tubule cells. Indeed, D1 dopamine receptors are present in the renal cortex, where they lead to an increase in [cAMP]i. The result is an inhibition of apical NHE3 in the proximal tubule and inhibition of the basolateral Na-K pump in multiple tubule segments. In humans, administering low doses of dopamine leads to natriuresis.
Elevated Plasma [Ca2+]
The kidney, similar to the parathyroid gland (see pp. 1060–1061), responds directly to changes in extracellular [Ca2+]. In the cortical TAL, an increase in basolateral [Ca2+] inhibits both the NKCC and K+ channels on the apical membrane (see Fig. 35-4B), thereby decreasing the lumen-positive Vte and reducing paracellular Na+ reabsorption. The mechanism appears to be the following (Fig. 35-14): Extracellular Ca2+ binds to a basolateral Ca2+-sensing receptor (CaSR), which couples to at least two G proteins. First, activation of Gαi decreases [cAMP]i, thus reducing stimulation of Na/K/Cl cotransport by cAMP (see p. 768). Second, activation of a member of the Gi/Go family stimulates phospholipase A2 (PLA2; see p. 62), thereby increasing levels of arachidonic acid and one of its cytochrome P-450 metabolites, probably 20-hydroxyeicosatetraenoic acid (20-HETE). The latter inhibits apical NKCCs and K+ channels. Third, CaSR activates Gαq, elevating levels of inositol 1,4,5-trisphosphate (IP3) and thus [Ca2+]i (see p. 58) and also stimulating protein kinase C (PKC; see pp. 60–61), which also inhibits Na/K/Cl cotransport. Regardless of the mechanism, inhibition of apical Na/K/Cl cotransport (1) lowers [Cl−]i and thus hyperpolarizes the basolateral membrane, and (2) lowers [K+]i and thus depolarizes the apical membrane. Together, these two effects reduce the lumen-positive Vte, thereby inhibiting the paracellular reabsorption of Na+ and, as we shall see below, Ca2+ (see p. 789) and Mg2+ (see p. 791). The CaSR is also present in the proximal tubule, the medullary TAL, the DCT, and the collecting ducts. N36-14
FIGURE 35-14 Role of CaSR in regulating Na+ reabsorption by the TAL. AC, adenylyl cyclase.
Endogenous Na-K Pump Inhibitor
Human plasma contains an endogenous ouabain-like steroid (see p. 117) that inhibits Na-K pumps in a wide variety of cells. Levels of this natural Na-K pump inhibitor increase with salt loading and it is present in high levels in patients with hypertension. In response to Na+ loading, the body may increase levels of this inhibitor, which presumably would bind preferentially to Na-K pumps of collecting-duct cells, thereby elevating [Na+]i and enhancing Na+ excretion.
Produced locally in the kidney, prostaglandin E2 (PGE2) inhibits Na+ reabsorption and promotes natriuresis. In the TAL, PGE2 inhibits both apical and basolateral K+ channels, depolarizing both membranes and reducing passive Cl− efflux across the basolateral membrane. [Cl−]i therefore rises, impeding the turnover of the apical NKCC2 (see Fig. 35-4B) and reducing NaCl reabsorption. In addition, the Vte becomes less lumen positive, which decreases the driving force for passive paracellular reabsorption of Na+ and other cations. In the CCT, both PGE2 and bradykinin inhibit electrogenic reabsorption of Na+ through principal cells (see Fig. 35-4D). Accordingly, drugs that inhibit prostaglandin synthesis (e.g., nonsteroidal anti-inflammatory drugs, or NSAIDs) tend to cause Na+ retention, resistance to diuretic drugs, and exacerbation of hypertension in some patients.
In the TAL, bradykinin—also made locally in the kidney—stimulates PGE2 synthesis and release, which in turn inhibits NaCl reabsorption (see above). Moreover, in the CCT, bradykinin inhibits ENaC activity, thereby reducing Na+ reabsorption and favoring natriuresis. Because angiotensin-converting enzyme (ACE) degrades bradykinin, one of the mechanisms by which ACE inhibitors enhance Na+ excretion and reduce blood pressure is blocking bradykinin breakdown.