Blood flow is variable between one organ and another, depending on the overall demands of each organ system (see Fig. 4-1). For example, blood flow to the lungs is equal to the cardiac output because allblood must pass through the lungs, allowing O2 to be added to it and CO2 to be removed from it. No other organ receives the entire cardiac output! The kidneys, gastrointestinal tract, and skeletal muscle all have high blood flow, each receiving approximately 25% of cardiac output. Other organs receive smaller percentages of the cardiac output. These interorgan differences in blood flow are the result of differences in vascular resistance.
Furthermore, blood flow to a specific organ or organ system can increase or decrease, depending on its metabolic demands. For example, exercising skeletal muscle has greater demand for O2 than does resting skeletal muscle. To meet the greater demand for O2, blood flow to skeletal muscle must temporarily increase above the resting level.
Changes in blood flow to an individual organ are achieved by altering arteriolar resistance. The mechanisms that regulate blood flow to the various organs are broadly categorized as local (intrinsic) control and neural or hormonal (extrinsic) control. Local control of blood flow is the primary mechanism utilized for matching blood flow to the metabolic needs of a tissue. Local control is exerted through the direct action of local metabolites on arteriolar resistance. Neural or hormonal control of blood flow includes such mechanisms as the action of the sympathetic nervous system on vascular smooth muscle and the actions of vasoactive substances such as histamine, bradykinin, and prostaglandins.
Mechanisms for Control of Regional Blood Flow
Local Control of Blood Flow
There are several examples of local (intrinsic) control of blood flow including autoregulation, active hyperemia, and reactive hyperemia. Each example of local control is discussed generally, followed by a more detailed explanation of the mechanism.
Autoregulation is the maintenance of a constant blood flow to an organ in the face of changing arterial pressure. Several organs exhibit autoregulation of blood flow including the kidneys, brain, heart, and skeletal muscle. For example, if arterial pressure in a coronary artery suddenly decreases, an attempt will be made to maintain constant blood flow through this coronary artery. Such autoregulation can be achieved by an immediate compensatory vasodilation of the coronary arterioles, decreasing the resistance of the coronary vasculature and keeping flow constant in the face of decreased pressure.
Active hyperemia illustrates the concept that blood flow to an organ is proportional to its metabolic activity. As noted previously, if metabolic activity in skeletal muscle increases as a result of strenuous exercise, then blood flow to the muscle will increase proportionately to meet the increased metabolic demand.
Reactive hyperemia is an increase in blood flow in response to or reacting to a prior period of decreased blood flow. For example, reactive hyperemia is the increase in blood flow to an organ that occurs following a period of arterial occlusion. During the occlusion, an O2 debt is accumulated. The longer the period of occlusion, the greater the O2 debt and the greater the subsequent increase in blood flow above the preocclusion levels. The increase in blood flow continues until the O2 debt is “repaid.”
Two basic mechanisms are proposed to explain the phenomena of autoregulation and active and reactive hyperemia: the myogenic hypothesis and the metabolic hypothesis.
Myogenic hypothesis. The myogenic hypothesis can be invoked to explain autoregulation, but it does not explain active or reactive hyperemia. The myogenic hypothesis states that when vascular smooth muscle is stretched, it contracts. Thus, if arterial pressure is suddenly increased, the arterioles are stretched and the vascular smooth muscle in their walls contracts in response to this stretch. Contraction of arteriolar vascular smooth muscle causes constriction (i.e., increased resistance), thereby maintaining a constant flow in the face of increased pressure (recall that Q = ΔP/R). Conversely, if arterial pressure suddenly decreases, there is less stretch on the arterioles, causing them to relax and arteriolar resistance to decrease. Thus, constant flow can be maintained in the face of increased or decreased arterial pressure by changing arteriolar resistance.
One can also think about the myogenic mechanism in terms of maintaining arteriolar wall tension. Blood vessels, such as arterioles, are built to withstand the wall tensions they normally “see.” In the example of a sudden increase in arterial pressure, the increased pressure, if unopposed, will cause an increase in arteriolar wall tension. Such an increase in wall tension is undesirable for the arteriole. Thus, in response to the stretch, arteriolar vascular smooth muscle contracts, decreasing the arteriolar radius and returning wall tension back to normal. This relationship is explained by the law of Laplace for a cylinder, which states that T = P × r. If pressure (P) increases and radius (r) decreases, then wall tension (T) can remain constant. (Of course, the other consequence of the decreased radius, discussed previously, is increased arteriolar resistance; in the face of increased pressure, increased resistance allows blood flow to be maintained constant, i.e., autoregulation.)
Metabolic hypothesis. The metabolic hypothesis can be invoked to explain each of the phenomena of local control of blood flow. The basic premise of this hypothesis is that O2 delivery to a tissue can be matched to O2consumption of the tissue by altering the resistance of the arterioles, which in turn alters blood flow. As a result of metabolic activity, the tissues produce various vasodilator metabolites (e.g.,CO2, H+, K+, lactate, and adenosine). The greater the level of metabolic activity, the greater the production of vasodilator metabolites. These metabolites produce vasodilation of arterioles, which decreases resistance and, therefore, increases flow to meet the increased demand for O2. The tissues vary according to which vasodilator metabolite is primarily responsible for vasodilation; for example, the coronary circulation is most sensitive to PO2 and adenosine, whereas the cerebral circulation is most sensitive to PCO2 (Table 4-7).
Table 4–7 Control of Special Circulations
The following two examples illustrate how the metabolic hypothesis explains active hyperemia: (1) The first example considers strenuous exercise. During strenuous exercise, metabolic activity in the exercising skeletal muscle increases and production of vasodilator metabolites, such as lactate, increases. These metabolites cause local vasodilation of skeletal muscle arterioles, which increases local blood flow and increases O2 delivery to meet the increased demand of the exercising muscle. (2) The second example considers a scenario in which there is a spontaneous increase in arterial pressure to an organ. Initially, the increased pressure will increase blood flow, which will deliver more O2 for metabolic activity and “wash out” vasodilator metabolites. As a result of this washout, there will be a local dilution of vasodilator metabolites, resulting in arteriolar vasoconstriction, increased resistance, and a compensatory decrease in blood flow back to the normal level.
Neural and Hormonal Control of Blood Flow
The most important example of neural (extrinsic) control of regional blood flow involves the sympathetic innervation of vascular smooth muscle in some tissues. The density of such sympathetic innervation varies widely from tissue to tissue. For example, blood vessels of the skin and skeletal muscle have a high density of sympathetic nerve fibers, whereas coronary, pulmonary, and cerebral vessels have little sympathetic innervation. It is important to note whether sympathetic innervation is absent or present and also, when present, whether it produces vasoconstriction or vasodilation (see Table 2-2). In skin, the sympathetic innervation produces vasoconstriction via α1 receptors. In skeletal muscle, when the sympathetic nervous system is activated, there can be vasoconstriction (sympathetic nerve fibers, α1 receptors) or vasodilation (epinephrine from adrenal medulla, β2 receptors).
Other vasoactive substances include histamine, bradykinin, serotonin, and prostaglandins. Histamine is released in response to trauma and has powerful vascular effects. Simultaneously, it causes dilation of arterioles and constriction of venules, with the net effect being a large increase in Pc, which increases filtration out of capillaries, and local edema. Bradykinin, like histamine, causes dilation of arterioles and constriction of venules, resulting in increased filtration out of capillaries and local edema. Serotonin is released in response to blood vessel damage and causes local vasoconstriction (in an attempt to reduce blood flow and blood loss). Serotonin has been implicated in the pathophysiology of vascular spasms that occur in migraine headache. The prostaglandins produce various effects on vascular smooth muscle. Prostacyclin and the prostaglandin-E series are vasodilators in many vascular beds. Thromboxane A2 and the prostaglandin-F series are vasoconstrictors. Angiotensin II and vasopressin (via V1 receptors) are potent vasoconstrictors that increase TPR. Atrial natriuretic peptide is a vasodilator hormone that is secreted by the atria in response to increases in atrial pressure.
Blood flow through the coronary circulation is controlled almost entirely by local metabolites, with sympathetic innervation playing only a minor role. The most important local metabolic factors are hypoxiaand adenosine. For example, if there is an increase in myocardial contractility, there is increased O2 demand by the cardiac muscle and increased O2 consumption, causing local hypoxia. This local hypoxia causes vasodilation of the coronary arterioles, which then produces a compensatory increase in coronary blood flow and O2 delivery to meet the demands of the cardiac muscle (i.e., active hyperemia).
An unusual feature of the coronary circulation is the effect of mechanical compression of the blood vessels during systole in the cardiac cycle. This compression causes a brief period of occlusion and reduction of blood flow. When the period of occlusion (i.e., systole) is over, reactive hyperemia occurs to increase blood flow and O2 delivery and to repay the O2 debt that was incurred during the compression.
The cerebral circulation is controlled almost entirely by local metabolites and exhibits autoregulation and active and reactive hyperemia. The most important local vasodilator in the cerebral circulation is CO2(or H+). An increase in cerebral PCO2 (producing an increase in H+ concentration and a decrease in pH) causes vasodilation of the cerebral arterioles, which results in an increase in blood flow to assist in removal of the excess CO2.
It is interesting that many circulating vasoactive substances do not affect the cerebral circulation because their large molecular size prevents them from crossing the blood-brain barrier.
The regulation of pulmonary circulation is discussed fully in Chapter 5. Briefly, the pulmonary circulation is controlled by O2. The effect of O2 on pulmonary arteriolar resistance is the exact opposite of its effect in other vascular beds: In the pulmonary circulation, hypoxia causes vasoconstriction. This seemingly counterintuitive effect of O2 also is explained in Chapter 5. Briefly, regions of hypoxia in the lung cause local vasoconstriction, which effectively shunts blood away from poorly ventilated areas where the blood flow would be “wasted” and toward well-ventilated areas where gas exchange can occur.
The regulation of renal blood flow is discussed in detail in Chapter 6. Briefly, renal blood flow is tightly autoregulated so that flow remains constant even when renal perfusion pressure changes. Renal autoregulation is independent of sympathetic innervation, and it is retained even when the kidney is denervated (e.g., in a transplanted kidney). Autoregulation is presumed to result from a combination of the myogenic properties of the renal arterioles and tubuloglomerular feedback (see Chapter 6).
Skeletal Muscle Circulation
Blood flow to skeletal muscle is controlled both by local metabolites and by sympathetic innervation of its vascular smooth muscle. Incidentally, the degree of vasoconstriction of skeletal muscle arterioles is a major determinant of TPR because the mass of skeletal muscle is so large, compared with that of other organs.
At rest, blood flow to skeletal muscle is regulated primarily by its sympathetic innervation. Vascular smooth muscle in the arterioles of skeletal muscle is densely innervated by sympathetic nerve fibers that are vasoconstricting (α1 receptors). There are also β2 receptors on the vascular smooth muscle of skeletal muscle that are activated by epinephrine and cause vasodilation. Thus, activation of α1 receptors causes vasoconstriction, increased resistance, and decreased blood flow. Activation of β2 receptors causes vasodilation, decreased resistance, and increased blood flow. Usually, vasoconstriction predominates because norepinephrine, released from sympathetic adrenergic neurons, stimulates primarily α1 receptors. On the other hand, epinephrine released from the adrenal gland during the fight-or-flight response or during exercise activates β2 receptors and produces vasodilation.
During exercise, blood flow to skeletal muscle is controlled primarily by local metabolites. Each of the phenomena of local control is exhibited: autoregulation and active and reactive hyperemia. During exercise, the demand for O2 in skeletal muscle varies with the activity level, and, accordingly, blood flow is increased or decreased to deliver sufficient O2 to meet the demand. The local vasodilator substances in skeletal muscle are lactate, adenosine, and K+.
Mechanical compression of the blood vessels in skeletal muscle can also occur during exercise and cause brief periods of occlusion. When the period of occlusion is over, a period of reactive hyperemia will occur, which increases blood flow and O2 delivery to repay the O2 debt.
The skin has blood vessels with dense sympathetic innervation, which controls its blood flow. The principal function of the sympathetic innervation is to alter blood flow to the skin for regulation of body temperature. For example, during exercise, as body temperature increases, sympathetic centers controlling cutaneous blood flow are inhibited. This selective inhibition produces vasodilation in cutaneous arterioles so that warm blood from the body core can be shunted to the skin surface for dissipation of heat. Local vasodilator metabolites have little effect on cutaneous blood flow.
The effects of vasoactive substances such as histamine have been discussed previously. In skin, the effects of histamine on blood vessels are visible. Trauma to the skin releases histamine, which produces atriple response in skin: a red line, a red flare, and a wheal. The wheal is local edema and results from histaminic actions that vasodilate arterioles and vasoconstrict veins. Together, these two effects produce increased Pc, increased filtration, and local edema.