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The Peripheral Circulation and Its Control


Objectives

  • 1.

    Indicate the intrinsic and extrinsic (neural and humoral) factors that regulate peripheral blood flow.

  • 2.

    Explain autoregulation of blood flow and the myogenic mechanism for local adjustments of blood flow.

  • 3.

    Elucidate metabolic regulation of blood flow.

  • 4.

    Explain the role of the sympathetic nerves in blood flow regulation.

  • 5.

    Describe vascular reflexes in the control of blood flow.

  • 6.

    Describe the role of humoral agents in the regulation of blood flow.

The Functions of the Heart and Large Blood Vessels

The principal function of the heart is to pump blood to the tissues of the body. However, the distribution of blood to the crucial regions of the body depends on the large and small arteries and arterioles. The regulation of peripheral blood flow is essentially under dual control: centrally, by the nervous system, and locally, in the tissues by the conditions in the immediate vicinity of the blood vessels. The relative importance of the central and local control mechanisms varies among tissues. In some areas of the body, such as the skin and the splanchnic regions, neural regulation of blood flow predominates; in other regions, such as the heart and the brain, local factors are dominant.

The small arteries and arterioles that regulate the blood flow throughout the body are called the resistance vessels . These vessels offer the greatest resistance to the flow of blood pumped to the tissues by the heart. As such, they are important in the maintenance of arterial blood pressure. Smooth muscle fibers are the main component of the walls of the resistance vessels (see Fig. 1.2 ). Hence the vessel lumen can vary from complete obliteration by strong contraction of the smooth muscle with infolding of the endothelial lining to maximal dilation by full relaxation of the smooth muscle. At any given time, some resistance vessels are closed by partial contraction (tone) of the arteriolar smooth muscle. If all the resistance vessels in the body dilated simultaneously, blood pressure would fall precipitously. Passive stretch of the microvessels by an increase in intravascular pressure decreases vascular resistance, whereas a decrease in intravascular pressure increases vascular resistance by recoil of the stretched vascular muscle.

Contraction and Relaxation of Arteriolar Vascular Smooth Muscle Regulate Peripheral Blood Flow

Vascular smooth muscle is responsible for the control of total peripheral resistance, arterial and venous tone, and the distribution of blood flow throughout the body. The smooth muscle cells are small, mononucleate, and spindle shaped. They are usually arranged in helical or circular layers around the large blood vessels and in a single circular layer around arterioles ( Fig. 9.1A and B ). Also, parts of endothelial cells project into the vascular smooth muscle layer ( myoendothelial junctions ) at various points along the arterioles (see Fig. 9.1C ). These projections suggest a functional interaction between endothelium and adjacent vascular smooth muscle.

Fig. 9.1, (A) Low-magnification electron micrograph of an arteriole in cross section (inner diameter of approximately 40 μm) in cat ventricle. The wall of the blood vessel is composed largely of vascular smooth muscle cells (SM) whose long axes are directed approximately circularly around the vessel. A single layer of endothelial cells (E) forms the innermost portion of the blood vessel. Connective tissue elements (CT) , such as fibroblasts and collagen, make up the adventitial layer at the periphery of the vessel; nerve bundles also appear in this layer (N) . EN, Endothelial cell nucleus. (B) Detail of the wall of the blood vessel in (A). This field contains a single endothelial layer (E) , the medial smooth muscle layer, with three smooth muscle cell profiles ( SM 1 , SM 2 , SM 3 ) , and the adventitial layer, containing nerves (N) and connective tissue (CT) . SMN, Smooth muscle nucleus. (C) Another region of the arteriole, showing the area in which the endothelial (E) and smooth muscle (SM) layers are apposed. A projection of an endothelial cell (between arrows ) is closely applied to the surface of the overlying smooth muscle, forming a myoendothelial junction. Plasmalemmal vesicles (V) are prominent in both the endothelium and the smooth muscle cell (where such vesicles are known as caveolae [C] ).

In general, the close association between action potentials and contraction observed in skeletal and cardiac muscle cells cannot be demonstrated in vascular smooth muscle. Also, vascular smooth muscle lacks transverse tubules. Graded changes in membrane potential are often associated with changes in force. Contractile activity is generally elicited by neural or humoral stimuli, and the activity of smooth muscle varies in different vessels. For example, some vessels, particularly in the portal or mesenteric circulation, contain longitudinally oriented smooth muscle. This muscle is spontaneously active, and it displays action potentials that are correlated with the contractions and the electrical coupling between cells.

Vascular smooth muscle cells contain large numbers of thin actin filaments and small numbers of thick myosin filaments. These filaments are aligned in the long axis of the cell, but they do not form visible sarcomeres with striations. Nevertheless, the sliding filament mechanism is believed to operate in this tissue, and phosphorylation of crossbridges regulates their rate of cycling. Compared with skeletal muscle, the smooth muscle contracts very slowly, develops high forces, and maintains force for long periods. The adenosine triphosphate (ATP) use is diminished, and it operates over a considerable range of lengths under physiological conditions. Cell-to-cell conduction occurs via gap junctions, as it does in cardiac muscle (see Chapter 3, Chapter 4 ).

In smooth muscle, the interaction between myosin and actin, which leads to contraction, is controlled by the myoplasmic Ca ++ concentration, as it is in cardiac and skeletal muscle. The molecular mechanism by which Ca ++ regulates contraction in smooth muscle ( Fig. 9.2 ) is fundamentally different, however, because smooth muscle does not use the Ca ++ -binding regulatory protein troponin. For smooth muscle crossbridges to be activated to cycle, the 20-kDa regulatory light chain of myosin (MLC 20 , a protein subunit of myosin) must be phosphorylated. MLC 20 is phosphorylated by myosin light-chain kinase (MLCK) and dephosphorylated by myosin light-chain phosphatase (MLCP). This requirement for phosphorylation aids regulation of contraction in smooth muscle in addition to that in cardiac and skeletal muscles, because both MLCK and MLCP are themselves regulated by other kinases. MLCK is activated by a complex between 4 Ca ++ and the Ca ++ -binding messenger protein calmodulin (CaM) , which is present in high abundance in smooth muscle cells. The concentration of Ca ++ /calmodulin, and thus the activation of MLCK, is driven by the cytoplasmic Ca ++ concentration (i.e., Ca ++ activation of contraction). However, the level of phosphorylation of MLC 20 is also determined by MLCP. Inhibiting the activity of MLCP increases contraction, even when cytoplasmic Ca ++ (and MLCK activity) does not change, because inhibition of MLCP increases phosphorylation of MLC 20 . Inhibition of MLCP activity thus increases the Ca ++ sensitivity of contraction. Conversely, stimulation of MLCP activity decreases MLC 20 phosphorylation and contraction, even at a constant level of Ca ++ , and thus decreases Ca ++ sensitivity of contraction.

Fig. 9.2, For smooth muscle actin-myosin crossbridges to cycle and generate force or shortening, the 20-kDa myosin regulatory light-chain subunit (MLC 20 ) of myosin must be phosphorylated. Phosphorylation of MLC 20 is controlled by myosin light-chain kinase (MLCK) and myosin light-chain phosphatase (MLCP) . MLCK activity is inhibited by protein kinase A (PKA) . MLCP activity is inhibited by Rho- kinase and CPI-17 (17-kDa C-kinase potentiated protein phosphatase-1 inhibitor). P i , Inorganic phosphate, released from MLC 20 -P by the phosphatase action of MLCP; PKA, cyclic adenosine monophosphate (AMP)–dependent protein kinase; PKG, cyclic guanosine monophosphate (GMP)–dependent protein kinase.

MLCP is inhibited primarily by rho -kinase (a regulator of the cytoskeleton in many types of cells). Rho -kinase is activated in a signaling cascade that begins with activation of certain G protein–coupled receptors (GPCRs) on the surface membrane. Another protein, CPI-17 (17-kDa C-protein–potentiated inhibitor of protein phosphatase), which is activated by protein kinase C (PKC), also inhibits MLCP. Activity of MLCP may also be increased, particularly by nitric oxide (NO), through cyclic GMP and protein kinase G (PKG), and by cyclic adenosine monophosphate (cAMP), acting through protein kinase A (PKA). The release of NO by endothelial cells, and subsequent stimulation of smooth muscle MLCP, constitutes a major mechanism by which endothelium may cause smooth muscle relaxation and arterial or venous dilation. In summary, regulation of smooth muscle contraction by neurotransmitters, circulating hormones, and autocoids often involves both changes in Ca ++ activation of contraction (MLCK) and in Ca ++ sensitivity of contraction (MLCP) (see later). The contractile state of smooth muscle is thus governed finally by the ratio of Ca ++ -activated MLCK activity to MLCP activity because this ratio determines the level of phosphorylation of MLC 20 .

Cytoplasmic Ca ++ Is Regulated to Control Contraction via Myosin Light-Chain Kinase

The cytoplasmic Ca ++ concentration, and thus MLCK activity, is determined by the summation of the Ca ++ that enters the cytosol (influx) and that leaving the cytosol (efflux) ( Fig. 9.3 ). Ca ++ enters the cytosol in two ways: (1) from the extracellular space via influx through voltage-operated calcium channels (typically L-type, activated by depolarization), receptor-operated calcium channels (ROCs, activated after the action of agonists on membrane receptors), and store-operated calcium channels (activated after depletion of sarcoplasmic reticulum Ca ++ stores); and (2) from the sarcoplasmic reticulum (SR) via activation of either ryanodine receptor channels (RyRs) or inositol-1,4,5 triphosphate (IP 3 ) receptor channels (IP 3 -stimulated) located on the SR. Ca ++ ions leave the cytosol via ATP-driven calcium transporters (i.e., Ca ++ pumps) located on both the SR (termed SERCAs) and plasma membrane (termed PMCAs) as well as activation of the Na + /Ca ++ exchangers on the plasma membrane, as in cardiac muscle (see Fig. 4.8 ).

Fig. 9.3, Control of cytoplasmic calcium ion ([Ca ++ ], shown as Ca 2+ here) in vascular smooth muscle. Calcium can enter the cell via electrically activated channels (e.g., voltage-operated Ca ++ channel, L-type Ca ++ channel), via receptor-operated channels (ROCs) in the sarcolemma, or via store-operated channels (SOCs) . SOCs open when the sarcoplasmic reticulum (SR) becomes depleted of Ca ++ . Calcium is also released from the sarcoplasmic reticulum through ryanodine receptor channels (RyRs) and through inositol triphosphate receptors (IP 3 Rs) in response to inositol triphosphate (IP 3 ) stimulation and is taken back into the SR by a calcium pump (SERCA) . Calcium is extruded from the cell by a plasma membrane calcium pump (PMCA) and by the Na + /Ca ++ exchanger (NCX) . Membrane potential is determined by K Ca channels, which may be activated by local Ca ++ and by ROCs, which are permeable to both Na + and Ca ++ . ADP, Adenosine diphosphate; ATP, adenosine triphosphate; MLCK, myosin light-chain kinase; MLCP, myosin light-chain phosphatase; P i , inorganic phosphate.

Contraction Is Controlled by Excitation-Contraction Coupling and/or Pharmacomechanical Coupling

Cellular responses to agonist vary among different blood vessels as well as smooth muscle types. This diversity arises partly from differences in ion channels that may be present (such as potassium and calcium channels important in excitation-contraction [E-C] coupling) and in agonist-specific receptors (such as those that bind angiotensin II, norepinephrine, serotonin, histamine, and acetylcholine) expressed on the plasma membrane of vascular smooth muscle.

Excitation-Contraction Coupling in Vascular Smooth Muscle

The potential across the plasma membrane of vascular smooth muscle is an important determinant of cytoplasmic Ca ++ level, and thus of the contractile state of vascular smooth muscle. The reason is that both entry of Ca ++ into the cell and extrusion of Ca ++ from the cell are voltage-dependent (involving voltage-dependent Ca ++ channels and Na + /Ca ++ exchanger [NCX]). Depolarization increases Ca ++ influx and decreases Ca ++ efflux. In many types of arteries, membrane potential is strongly influenced by the transmural pressure (i.e., the blood pressure) through the myogenic mechanism (discussed later in this chapter), with increases in pressure tending to cause depolarization and consequent entry of Ca ++ through voltage-dependent Ca ++ channels. Membrane potential is, however, always strongly influenced by K + channels, with activation of K + channels tending to hyperpolarize the membrane and inhibition of K + channels tending to depolarize it. Some types of vascular smooth muscle produce action potentials in which the depolarizing current is carried by voltage-dependent (L-type) Ca ++ channels. The resting membrane potential of vascular smooth muscle is determined primarily by K + permeability because of the relative abundant expression of K + channels. Stimuli that open K + channels can alter membrane potential by altering K + efflux across the plasma membrane (because resting potassium concentration inside the cell, [K + ] i , is greater than that outside the cell, [K + ] o ). Opening of K + channels causes hyperpolarization (because of increased K + efflux) of the membrane, whereas closure of K + channels causes depolarization (because of decreased K + efflux). L-type calcium channels are voltage-sensitive and are activated (i.e., opened) by membrane depolarization, resulting in influx of extracellular Ca ++ and elevating intracellular Ca ++ concentration. If the increase in Ca ++ levels is sufficient, then the Ca ++ /calmodulin complex activates MLCK, promoting actin-myosin interaction and contraction. Thus changes in membrane potential alter extracellular Ca ++ influx and efflux; modulate intracellular cytoplasmic Ca ++ ; and affect vascular smooth muscle contraction, artery diameter, and vascular resistance.

Pharmacomechanical Coupling

Contraction of arteries and veins is very importantly modulated by hormones, neurotransmitters, and autocoids acting on receptors located in the plasma membrane ( Fig. 9.4 ). Most of these receptors are GPCRs. Pharmacomechanical (PM) coupling is a mechanism of contractile activation that causes little or no change in membrane potential (making it distinct from E-C coupling). PM coupling can result either in contraction (see Fig. 9.4A ) or relaxation (see Fig. 9.4B ). The three major components of PM coupling are (1) the GPCR itself, (2) the coupling complex, and (3) the second messenger (e.g., cAMP or IP 3 ). G protein–coupled receptors are characterized by the ligands they bind (e.g., adrenergic [catecholamines], serotonergic [serotonin], cholinergic [acetylcholine]) and by the particular heterotrimeric G proteins to which they are coupled. Important G proteins coupled to GPCRs on vascular smooth muscle cells include Gα q/11 , Gα 12/13 , Gα s , and Gα i/o . The G protein α subunits, and sometimes the G protein βγ subunits, activate specific effector molecules, such as kinases. In many cases, second messenger molecules are ultimately generated that stimulate downstream cellular mechanisms (ion influx, Ca ++ release, enzyme activation or inhibition). G protein–coupled receptors are important regulators of cardiovascular function, with many drugs acting on them. (An estimated 40% of currently used drugs act on GPCRs in the cardiovascular system and elsewhere in the body.)

Fig. 9.4, Key physiological neurotransmitters and hormones that control vascular tone, their receptors and intracellular mechanisms. (A) Physiological agonists bind to G protein–coupled receptors (GPCRs) that are coupled to different G proteins and to different effector molecules and second messengers. These pathways all result in vasoconstriction. The α subunits of the G-proteins are Gα q/11 , Gα 12/13 , and Gα i/o . AC, Adenyl cyclase; CaM, calmodulin; CPI-17, 17-kDa C-protein–potentiated inhibitor of protein phosphatase; DAG, diacylglycerol; IP 3 , inositol triphosphate; MLC 20 , 20-kDa myosin regulatory light chain; MLCK, myosin light-chain kinase; MLCP, myosin light-chain phosphatase (also known as protein phosphatase); PKC, protein kinase C; PLC-β, phospholipase C-β. (B) Epinephrine binds to the GPCR β 2 -AR (β 2 -adrenoceptor, AR) to promote vasodilation through increased cyclic adenosine monophosphate (cAMP) and activation of K + channels. β 2 -AR is coupled to the G-protein Gα S , which inhibits MLCK via phosphorylation by its effector, cAMP-dependent protein kinase A (PKA) .

Control of Vascular Tone by Catecholamines

The catecholamines norepinephrine (NE) and epinephrine are key controllers of cardiovascular function. Norepinephrine is released from sympathetic nerve endings in the heart and blood vessels and acts locally, whereas epinephrine is released from the adrenal medulla and circulates in the blood to act widely throughout the body. In general, the GPCRs that bind catecholamines are known as adrenoceptors because these receptors all bind the adrenal medullary hormones, epinephrine, and NE, although with varying affinities. The adrenoceptors are a large and diverse family of GPCRs, consisting of five major types (α 1 , α 2 , β 1 , β 2 , β 3 ) and several subtypes, and a full discussion of their function and pharmacology is reserved for pharmacology texts. In arteries and veins, NE binds most strongly to α 1 -adrenoceptors (α 1 -ARs), which are GPCRs located in the sympathetic neuroeffector junctions, on the smooth muscle cell membrane. These receptors couple to both Gα q/11 and Gα 12/13 (see Fig. 9.4A ), and their activation results in contraction (PM coupling). Gα q/11 activates phospholipase C (PLC), which catalyzes the production of diacylglycerol (DAG) and IP 3 from PIP 2 (phosphatidylinositol 4,5-bisphosphate). DAG activates PKC, which in turn activates CPI-17, which inhibits MLCP. IP 3 activates IP 3 receptors (IP 3 Rs) on the SR membrane to release Ca ++ , which binds to CaM and activates MLCK. Thus phosphorylation of MLC 20 is increased as a result of increased “Ca ++ activation” of contraction, and as a result of increased Ca ++ sensitivity of contraction. Release of NE from sympathetic nerve endings, and the subsequent contraction of vascular smooth muscle, is a major way in which vascular resistance and vascular capacitance (through contraction of small veins) are regulated. (Note that heart tissue contains few α 1 -ARs, and there NE acts primarily on β 1 receptors, which are coupled to Ga s , increasing cAMP and strengthening cardiac contraction (see Figs 5.23, Figs 5.28 ). Many vascular tissues contain few or no β 1 -ARs). Most of the arteries and veins of the body are innervated solely by fibers of the sympathetic nervous system; thus neurally released NE plays a major role in controlling vascular function through sympathetic nerve activity directed by the central nervous system. The sympathetic nerve fibers release NE to exert a tonic vasoconstrictor effect on the blood vessels, as evidenced by the fact that cutting or freezing the sympathetic nerves to a vascular bed (such as muscle) increases the blood flow. Activation of the sympathetic nerves either directly or reflexly enhances vascular resistance. (In contrast to the sympathetic nerves, the parasympathetic nerves tend to decrease vascular resistance. However, these nerves innervate only a small fraction of the blood vessels in the body, mainly in certain viscera and pelvic organs.)

Epinephrine is released from the adrenal medulla and circulates in the blood. Epinephrine acts most potently on β 2 -ARs on vascular smooth muscle and causes vasodilation through increases in cAMP (see Fig. 9.4B ) and reduced Ca ++ sensitivity of contraction. At very high concentrations in the plasma, however, epinephrine also binds to α 1 -ARs to cause contraction and vasoconstriction, overriding its effects mediated by the vascular β 2 -ARs. In the heart, both epinephrine and NE bind equally well to β 1 -ARs.

Control of Vascular Contraction by Other Hormones, Other Neurotransmitters, and Autocoids

Angiotensin II has many actions, most acting to increase arterial blood pressure. It is a direct vasoconstrictor, acting primarily on AT 1 receptors, which are coupled to both Gα q/11 and Gα 12/13 (see Fig. 9.4A ). Endothelin, a 21–amino acid peptide, acts primarily on ET A receptors on vascular smooth muscle to cause vasoconstriction (see Fig. 9.4A ). Endothelin is synthesized and released from endothelial cells. Vasopressin, or antidiuretic hormone (ADH), is a neurohypophysial hormone that is a potent constrictor. It is called into play to elevate blood pressure (and conserve fluid volume) particularly as a compensatory mechanism in hemorrhage. Vasopressin binds primarily to the V1 A receptor, which is coupled to Gα q/11 and Gα 2/13 . Neuropeptide Y is a sympathetic neurotransmitter that is coreleased with NE from sympathetic nerve endings on vascular smooth muscle and binds primarily to the Y 1 receptor, which is coupled to Gα i/o . Activation of Y 1 thus can decrease cAMP and enhance contraction by decreasing the PKA-mediated inhibition of MLCP.

Intrinsic Control of Peripheral Blood Flow

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