Perhaps the most impressive characteristic of the blood flow to skeletal muscle is its extreme range. Muscle blood flow at rest is 5 to 10 mL/min for each 100 g of tissue. With maximal aerobic exercise, it may increase 50-fold, reaching 250 mL/min or more for each 100 g of active muscle. The linear correspondence among work rate, O2 consumption, and muscle blood flow implies a “coupling” between muscle fiber activity and O2 delivery to capillaries. We discuss muscle blood flow during exercise beginning on page 1214. Here we discuss the key features of the organization of the skeletal muscle vasculature and the integration of its blood flow control mechanisms.
A microvascular unit is the capillary bed supplied by a single terminal arteriole
The vascular supply to skeletal muscle begins externally to the tissue in the feed arteries. These muscular vessels are the last branches of the arterial supply, located just before entry into the tissue. As much as 30% to 50% of the total resistance to blood flow of skeletal muscle resides in these feed arteries. Therefore, an important site of blood flow control is located proximally to the microvessels within the tissue that are in direct contact with skeletal muscle fibers.
The arteriolar network originates from the site at which a feed artery enters the muscle. Within the muscle, arterioles branch through several orders (Fig. 24-5A) until reaching the terminal arterioles (see Fig. 24-5B), which are the last branches to contain smooth muscle and, therefore, the last branches still able to control blood flow. Thus, the terminal arteriole is the functional equivalent of the precapillary sphincter (see p. 461). The group of capillaries supplied by a terminal arteriole represents one microvascular unit, which is the smallest functional unit of blood flow control in skeletal muscle. Each unit consists of 15 to 20 capillaries that run parallel to the muscle fibers in each direction, for a distance of ≤1 mm, ending in a collecting venule.
FIGURE 24-5 Microvascular units in skeletal muscle. A, A feed artery branches into primary arterioles, which, after two more orders of branching, give rise to transverse arterioles; the latter, in turn, give rise to terminal arterioles. B, The terminal arteriole supplies a “microvascular unit” (<1 mm in length).
Owing to the profound differences in length between capillaries (≤1 mm) and muscle fibers (centimeters), many microvascular units are required to span the distance of each muscle fiber. When a muscle fiber contracts, blood flow must increase throughout all of the microvascular units that supply that fiber to provide O2 and to remove metabolites (Box 24-1).
Treating Coronary Artery Disease
For many patients with gradual narrowing of the coronary arteries by atherosclerotic plaque, the first sign of disease may be the development of angina pectoris. Pain results when the metabolic demands of a region of myocardium exceed the ability of the compromised blood supply to satisfy those needs. Attacks of angina are often accompanied by characteristic changes on the electrocardiogram. If the diagnosis is in doubt—the chest pain of angina can sometimes be mimicked by gastroesophageal reflux, hyperventilation, costochondritis, and other clinical entities—an exercise test may stress the heart sufficiently to bring on the pain, to induce electrocardiographic changes, or to alter coronary blood flow as monitored by thallium scanning (see p. 426). Some patients with significant coronary artery narrowing never experience angina and are said to have silent ischemia. In these patients, only an astute clinician may detect the coronary disease.
Many patients with a stable anginal pattern respond well to medication. Nitrates induce vasodilation by releasing NO (see p. 67). The nitrates dilate peripheral veins, reducing venous return and thus the preload to the heart (see p. 526); they also dilate the arteries and arterioles, reducing blood pressure and therefore the afterload. Finally, nitrates may increase coronary collateral flow to the involved region of myocardium (however, see discussion of coronary steal on p. 562). Beta blockers prevent the sympathetic nervous system from stimulating myocardial β1 receptors, thereby reducing both heart rate and contractility. Calcium channel blockers lessen the contractility of the heart muscle and the vascular smooth muscle. These interventions all reduce the metabolic demands of the heart.
In patients for whom medication cannot control the angina, or who develop a pattern of unstable angina with an increasing frequency and severity of anginal attacks, mechanical revascularization may be required. For a long time, the only option was coronary artery bypass grafting, but nowadays percutaneous transluminal coronary angioplasty may often be successful. A cardiologist can perform this procedure at the same time as a diagnostic coronary artery catheterization. The physician advances a balloon-tipped catheter through a peripheral artery into the left ventricle and then loops the catheter back out the left ventricle to have a favorable angle for entering the coronary vessels from the aorta. Inflation of the balloon at the site of the obstruction flattens the plaque into the wall of the vessel and restores blood flow. The obstruction often recurs due to proliferation of VSMCs. Refinements in the technique, the placement of stents at the treated site, and the use of aggressive anticoagulation therapy have all contributed to the technique's growing success. Variants of this technique, in which lasers are used to remove the obstruction, are promising new approaches.
Given the continued prevalence of coronary artery disease, a great deal of research has been aimed at developing alternatives to medication and mechanical revascularization. Among the most promising of these is the use of angiogenesis promoters to stimulate the growth of new blood vessels for collateral blood flow (see pp. 481–482).
Metabolites released by active muscle trigger vasodilation and an increase in blood flow
When skeletal muscle is at rest, its vascular resistance is high, blood flow is low, and the venous O2 content is only a few milliliters per deciliter lower than the arterial O2 content. As exercise begins, the terminal arterioles (those closest to the capillaries) dilate first. This vasodilation increases blood flow through capillaries that are already flowing with blood and opens up previously unperfused capillaries, thus increasing the number of perfused capillaries and thereby decreasing the effective intercapillary distance (see Fig. 20-4B, C). Even before total blood flow increases very much, the greater demand of active muscle fibers for O2 produces a large increase in the O2 extraction ratio (see p. 464). As metabolic demand continues to increase, additional O2 delivery is required.
The vasculature meets increased metabolic demand by progressively dilating the more proximal arteriolar branches and feed arteries. Thus, vasodilation “ascends” the resistance network as metabolic demand increases. A coordinated vasodilation throughout the resistance network is essential when segments having substantial resistance are organized in series with each other. Dilation of the downstream arterioles, without dilation of the proximal arterioles and feed arteries, would result in only a limited ability to increase muscle blood flow because of the high resistance of upstream vessels. Thus, when feed arteries dilate in concert with arterioles, the increase in muscle blood flow is profound.
The primary stimulus triggering vasodilation is the release of vasodilator substances (e.g., adenosine, CO2, K+) from active muscle fibers in proportion to the energy expenditure. These metabolites diffuse locally and—acting either directly on VSMCs or indirectly on adjacent endothelial cells—relax the VSMCs of resistance vessels, thereby increasing blood flow in proportion to local demand. Although a variety of substances released by muscle fibers can contribute to the hyperemia, no single stimulus yet explains the integrated response of blood flow control to muscle contraction. Furthermore, the hyperemic response to increased muscle activity begins within a second or two of the onset of exercise. In contrast, it would take several seconds for these substances to be produced by the skeletal muscle fibers, to reach the interstitium, and to diffuse to the arteriolar VSMCs in sufficient concentration to elicit vasodilation.
The initiation of muscle fiber contraction leads to a release of K+ that may hyperpolarize N24-6 the VSMCs and endothelial cells of nearby arterioles (see Table 20-9). Once triggered, this electrical signal spreads from cell to cell through gap junctions along the endothelium and into VSMCs, conducting upstream to the larger vessels and causing them to dilate in concert. This mechanism of conducted vasodilation, together with the action of the muscle pump (see p. 565), contributes to the rapid onset of hyperemia. Increases in levels of other metabolites (e.g., adenosine and CO2 levels) or decreases in contribute to and sustain vasodilation and maintain the hyperemic response.
Vasodilation Caused by Increases in [K+]o
Contributed by Emile Boulpaep
Why does the transient increase in [K+]o cause a transient paradoxical hyperpolarization, rather than the depolarization that one might expect from the Nernst equation (see Equation 6-5)?
First of all, the effect is transient because the increase in [K+]o is short-lived—the ensuing vasodilation will wash away the excess extracellular K+.
Second, the rise in [K+]o causes Vm (membrane potential) to become more negative (a hyperpolarization) even though EK (the equilibrium potential for K+) becomes more positive (see Equation 6-5). The reason is that the K+ conductance of VSMCs depends largely on inwardly rectifying K+ channels (Kir channels; see Fig. 7-20). A peculiar property of Kir channels is that an increase in [K+]o not only causes EK to shift to more positive values, but also increases the slope conductance (i.e., the slope of the current-voltage relationship at EK). VSMCs normally do not live at EK, but at more positive voltages (−30 to −40 mV), reflecting the contributions from other conductances (e.g., Na+) with more positive equilibrium potentials. In the text, we introduced Equation 6-12 (shown here as Equation NE 24-1):
Here, GK, GNa, GCa, GCl, etc. represent membrane conductances for each ion, whereas Gm represents the total membrane conductance. Thus, GK/Gm represents the fractional conductance for K+. Therefore, the equation tells us that Vm not only depends on the various equilibrium potentials, but also on their respective fractional conductances. Thus, if an increase in [K+]o simultaneously causes (1) a slight decrease in the absolute value of EK and (2) a larger increase GK, the absolute value of the product (GK/Gm)EK will be larger. Because (GK/Gm)EK is a negative number, the net effect is that the computed value of Vm is more negative (i.e., a hyperpolarization).
In principle, a second phenomenon can contribute to the hyperpolarization. The increase in [K+]o will enhance the activity of the electrogenic Na-K pump, resulting an increase in the pump's outward current, and therefore a hyperpolarization.
Sympathetic innervation increases the intrinsic tone of resistance vessels
Sympathetic nerve fibers invest the entire resistance network of skeletal muscle, from feed arteries to terminal arterioles. The release of norepinephrine by these nerve terminals activates α-adrenoceptors on VSMCs, leading to vasoconstriction beyond that produced by transmural pressure and myogenic tone. On the other hand, the shear stress of blood flowing past the endothelial cells produces vasodilators, such as NO. The interactions among these vasoconstrictor and vasodilatory mechanisms maintain the intrinsic basal tone of the VSMCs. Venules also constrict in response to sympathetic nerve stimulation but are not directly innervated, and instead respond to norepinephrine that diffuses from the nearby arterioles.
With nearly one third of total body mass composed of skeletal muscle, the sympathetic control of vasomotor tone to skeletal muscle is an integral component of the regulation of both systemic arterial pressure (via total peripheral resistance) and cardiac filling (via venous capacitance and return). This principle is particularly relevant during maximal aerobic exercise (see pp. 1213–1215), when the majority of cardiac output flows to the active skeletal muscles.
The basal firing rate of the sympathetic nerves to skeletal muscle is 1 to 2 Hz, which contributes only modestly to the resting vasomotor tone. However, with the onset of exercise, or when high-pressure baroreceptors detect a fall in blood pressure (see pp. 534–536), sympathetic firing to skeletal muscle resistance vessels may increase to 8 to 16 Hz. This degree of sympathetic nerve activity can close the lumens of arterioles in resting skeletal muscle. However, during exercise arterioles remain dilated under the influence of vasodilator metabolites released from surrounding muscle fibers. Because feed arteries are external to the muscle, enhanced sympathetic tone can limit total flow into the muscle and thereby help to maintain arterial pressure.
During exercise, total blood flow through skeletal muscle increases to as much as 80% of cardiac output. This redistribution of systemic blood flow occurs for two reasons. First, the increase in sympathetic nerve activity constricts the splanchnic circulation (see below), renal circulation (see p. 752), and the vessels of inactive skeletal muscle. Indeed, only the brain and heart are spared from vasoconstriction. Second, the metabolites released by active skeletal muscle overcome the constriction of arterioles that sympathetic activity would otherwise produce. In addition, substances released during muscle fiber contraction (e.g., NO and adenosine) may inhibit norepinephrine release from sympathetic nerve fibers surrounding the arterioles.
The vasodilatory effects of the metabolites notwithstanding, sympathetic vasoconstrictor activity can limit muscle blood flow, particularly when another large mass of muscle is active simultaneously and requires a substantial portion of cardiac output. Thus, during “whole-body” exercise, each muscle group may receive only a fraction of the blood flow it would otherwise get if it were the only active group in the body. It is at the level of the feed arteries—which are external to the muscle and thus physically removed from the direct influence of the vasoactive products of muscular activity—that sympathetic vasoconstriction puts an upper limit on blood flow during intense aerobic exercise. At the same time, dilation of arterioles within the active muscle maximizes O2 extraction by promoting capillary perfusion.
Rhythmic contraction promotes blood flow through the “muscle pump”
During exercise, skeletal muscle undergoes rhythmic changes in length and tension, giving rise to mechanical forces within the tissue analogous to those of the beating heart. The contraction of muscle forces venous blood out of the muscle and impedes arterial inflow (Fig. 24-6). Because valves in the veins prevent backflow of blood, each muscle contraction squeezes and empties the veins, driving blood toward the heart (see p. 516). During the subsequent relaxation, the reduction in venous pressure increases the arteriovenous driving force for capillary perfusion. As is true for coronary blood flow, skeletal muscle blood flow is maximal between contractions. This pumping action of skeletal muscle on the vasculature imparts substantial kinetic energy to the blood, thereby reducing the work of the heart. Remarkably, the skeletal muscle pump may generate up to half of the total energy required to circulate blood, an essential contribution for achieving the high blood flows experienced during maximal aerobic exercise. In contrast, drugs that dilate blood vessels of inactive muscle (i.e., muscle lacking a muscle pump) increase blood flow to a lesser extent than do rhythmic contractions.
FIGURE 24-6 Muscle pump.