is a term commonly used to characterize the general contractile state of a vessel or a vascular region. The “vascular tone” of a region can be taken as an indication of the “level of activation” of the individual smooth muscle cells in that region. As described in Chapter 6
, the blood flow through any organ is determined largely by its vascular resistance, which is dependent primarily on the diameter of its arterioles. Consequently, an organ’s flow is controlled by factors that influence the arteriolar smooth muscle tone.
Arterioles remain in a state of partial constriction even when all external influences on them are removed; hence, they are said to have a degree of basal tone (sometimes referred to as intrinsic tone). The understanding of the mechanism is incomplete, but basal arteriolar tone may be a reflection of the fact that smooth muscle cells inherently and actively resist being stretched as they continually are in pressurized arterioles. Another hypothesis is that the basal tone of arterioles is the result of a tonic production of local vasoconstrictor substances by the endothelial cells that line their inner surface. In any case, this basal tone establishes a baseline of partial arteriolar constriction from which the external influences on arterioles exert their dilating or constricting effects. These influences can be separated into three categories: local influences, neural influences, and hormonal influences.
Local Influences on Arterioles
The arterioles that control flow through a given organ lie within the organ tissue itself. Thus, arterioles and the smooth muscle in their walls are exposed to the chemical composition of the interstitial fluid of the organ they serve. The interstitial concentrations of many substances reflect the balance between the metabolic activity of the tissue and its blood supply. Interstitial oxygen levels, for example, fall whenever the tissue cells are using oxygen faster than it is being supplied to the tissue by blood flow. Conversely, interstitial oxygen levels rise whenever excess oxygen is being delivered to a tissue from the blood. In nearly all vascular beds, exposure to low oxygen reduces arteriolar tone and causes vasodilation, whereas high oxygen levels cause arteriolar vasoconstriction.3
Thus, a local feedback mechanism exists that automatically operates on arterioles to regulate a tissue’s blood flow in accordance with its metabolic needs. Whenever blood flow and oxygen delivery fall below a tissue’s oxygen demand, the oxygen levels around arterioles fall, the arterioles dilate, and the blood flow through the organ appropriately increases.
Many substances in addition to oxygen are present within tissues and can affect the tone of the vascular smooth muscle. When the metabolic rate of skeletal muscle is increased by exercise, tissue levels of oxygen decrease, but those of carbon dioxide, H+, and K+ increase. Muscle tissue osmolarity also increases during exercise. All these chemical alterations cause arteriolar dilation. In addition, with increased metabolic activity or oxygen deprivation, cells in many tissues may release adenosine, which is an extremely potent vasodilator agent.
At present, it is not known which of these (and possibly other) metabolically related chemical alterations within tissues are most important in the local metabolic control of blood flow. It appears likely that arteriolar tone depends on the combined action of many factors.
For conceptual purposes, Figure 7–2 summarizes current understanding of local metabolic control. Vasodilator factors enter the interstitial space from the tissue cells at a rate proportional to tissue metabolism. These vasodilator factors are removed from the tissue at a rate proportional to blood flow. Whenever tissue metabolism is proceeding at a rate for which the blood flow is inadequate, the interstitial vasodilator factor concentrations automatically build up and cause the arterioles to dilate. This, of course, causes blood flow to increase. The process continues until blood flow has risen sufficiently to appropriately match the tissue metabolic rate and prevent further accumulation of vasodilator factors. The same system also operates to reduce blood flow when it is higher than required by the tissue’s metabolic activity, because this situation causes a reduction in the interstitial concentrations of metabolic vasodilator factors.
Local metabolic vasodilator hypothesis.
Local metabolic mechanisms represent by far the most important means of local flow control. By these mechanisms, individual organs are able to regulate their own flow in accordance with their specific metabolic needs.
As indicated below, several other types of local influences on blood vessels have been identified. However, many of these represent fine-tuning mechanisms and many are important only in certain, usually pathological, situations.
Local Influences from Endothelial Cells
Endothelial cells cover the entire inner surface of the cardiovascular system. A large number of studies have shown that blood vessels respond very differently to certain vascular influences when their endothelial lining is missing. Acetylcholine, for example, causes vasodilation of intact vessels but causes vasoconstriction of vessels stripped of their endothelial lining. This and similar results led to the realization that endothelial cells can actively participate in the control of arteriolar diameter by producing local chemicals that affect the tone of the surrounding smooth muscle cells. In the case of the vasodilator effect of infusing acetylcholine through intact vessels, the vasodilator influence produced by endothelial cells has been identified as nitric oxide. Nitric oxide is produced within endothelial cells from the amino acid, L-arginine, by the action of an enzyme, nitric oxide synthase. Nitric oxide synthase is activated by a rise in the intracellular level of the Ca2+. Nitric oxide is a small lipid-soluble molecule that, once formed, easily diffuses into adjacent smooth muscle cells where it causes relaxation by stimulating cGMP production as mentioned previously.
Acetylcholine and several other agents (including bradykinin, vasoactive intestinal peptide, and substance P) stimulate endothelial cell nitric oxide production because their receptors on endothelial cells are linked to receptor-operated Ca2+ channels. Probably more importantly from a physiological standpoint, flow-related shear stresses on endothelial cells stimulate their nitric oxide production presumably because stretch-sensitive channels for Ca2+ are activated. Such flow-related endothelial cell nitric oxide production may explain why, for example, exercise and increased blood flow through muscles of the lower leg can cause dilation of the blood-supplying femoral artery at points far upstream of the exercising muscle itself.
Agents that block nitric oxide production by inhibiting nitric oxide synthase cause significant increases in the vascular resistances of most organs. For this reason, it is believed that endothelial cells are normally always producing some nitric oxide that is importantly involved, along with other factors, in reducing the normal resting tone of arterioles throughout the body.
Endothelial cells have also been shown to produce several other locally acting vasoactive agents including the vasodilators “endothelial-derived hyperpolarizing factor”, prostacyclin and the vasoconstrictor endothelin. Endothelin in particular is the topic of intense current research. It has the greatest vasoconstrictor potency of any known substance and appears to have many other biological effects as well. Much recent evidence suggests that endothelin may play important roles in such important overall process such as bodily salt handling and blood pressure regulation.
One general unresolved issue with the concept that arteriolar tone (and therefore local nutrient blood flow) is regulated by factors produced by arteriolar endothelial cells is how these cells could know what the metabolic needs of the downstream tissue are. This is because the endothelial cells lining arterioles are exposed to arterial blood whose composition is constant regardless of flow rate or what is happening downstream. One hypothesis is that there exists some sort of communication system between vascular endothelial cells. That way, endothelial cells in capillaries or venules could telegraph upstream information about whether the blood flow is indeed adequate.
Other Local Chemical Influences
In addition to local metabolic influences on vascular tone, many specific locally-produced and locally-reacting chemical substances have been identified that have vascular effects and therefore could be important in local vascular regulation in certain instances. In most cases, however, definite information about the relative importance of these substances in cardiovascular regulation is lacking.
Prostaglandins and thromboxane are a group of several chemically related products of the cyclooxygenase pathway of arachidonic acid metabolism. Certain prostaglandins are potent vasodilators, whereas others are potent vasoconstrictors. Despite the vasoactive potency of the prostaglandins and the fact that most tissues (including endothelial cells and vascular smooth muscle cells) are capable of synthesizing prostaglandins, it has not been demonstrated convincingly that prostaglandins play a crucial role in normal vascular control. It is clear, however, that vasodilator prostaglandins are involved in inflammatory responses. Consequently, inhibitors of prostaglandin synthesis, such as aspirin, are effective anti-inflammatory drugs. Prostaglandins produced by platelets and endothelial cells are important in the hemostatic (flow stopping, antibleeding) vasoconstrictor and platelet-aggregating responses to vascular injury. Hence, aspirin is often prescribed to reduce the tendency for blood clotting—especially in patients with potential coronary flow limitations. Arachidonic acid metabolites produced via the lipoxygenase system (eg, leukotrienes) also have vasoactive properties and may influence blood flow and vascular permeability during inflammatory processes.
Histamine is synthesized and stored in high concentrations in secretory granules of tissue mast cells and circulating basophils. When released, histamine produces arteriolar vasodilation (via the cAMP pathway) and increases vascular permeability, which leads to edema formation and local tissue swelling. Histamine increases vascular permeability by causing separations in the junctions between the endothelial cells that line the vascular system. Histamine release is classically associated with antigen–antibody reactions in various allergic and immune responses. Many drugs and physical or chemical insults that damage tissue also cause histamine release. Histamine can stimulate sensory nerve endings to cause itching and pain sensations. Although clearly important in many pathological situations, it seems unlikely that histamine participates in normal cardiovascular regulation.
Bradykinin is a small polypeptide that has approximately ten times the vasodilator potency of histamine on a molar basis. It also acts to increase capillary permeability by opening the junctions between endothelial cells. Bradykinin is formed from certain plasma globulin substrates by the action of an enzyme, kallikrein, and is subsequently rapidly degraded into inactive fragments by various tissue kinases. Like histamine, bradykinin is thought to be involved in the vascular responses associated with tissue injury and immune reactions. It also stimulates nociceptive nerves and may thus be involved in the pain associated with tissue injury.
The passive elastic mechanical properties of arteries and veins and how changes in transmural pressure affect their diameters are discussed in Chapter 6. The effect of transmural pressure on arteriolar diameter is more complex because arterioles respond both passively and actively to changes in transmural pressure. For example, a sudden increase in the internal pressure within an arteriole produces (1) first an initial slight passive mechanical distention (slight because arterioles are relatively thick-walled and muscular), and (2) then an active constriction that, within seconds, may completely reverse the initial distention. A sudden decrease in transmural pressure elicits essentially the opposite response, that is, an immediate passive decrease in diameter followed shortly by a decrease in active tone, which returns the arteriolar diameter to near that which existed before the pressure change. The active phase of such behavior is referred to as a myogenic response, because it seems to originate within the smooth muscle itself. The mechanism of the myogenic response is not known for certain, but stretch-sensitive ion channels on arteriolar vascular smooth muscle cells are likely candidates for involvement.
All arterioles have some normal distending pressure to which they are probably actively responding. Therefore, the myogenic mechanism is likely to be a fundamentally important factor in determining the basal tone of arterioles everywhere. Also, for obvious reasons and as soon discussed, the myogenic response is potentially involved in the vascular reaction to any cardiovascular disturbance that involves a change in arteriolar transmural pressure.
Flow Responses Caused by Local Mechanisms
In organs with a highly variable metabolic rate, such as skeletal and cardiac muscles, the blood flow closely follows the tissue’s metabolic rate. For example, skeletal muscle blood flow increases within seconds of the onset of muscle exercise and returns to control values shortly after exercise ceases. This phenomenon, which is illustrated in Figure 7–3A, is known as exercise or active hyperemia (hyperemia means high flow). It should be clear how active hyperemia could result from the local metabolic vasodilator feedback on the arteriolar smooth muscle. As alluded to previously, once initiated by local metabolic influences on small resistance vessels, endothelial flow-dependent mechanisms may assist in propagating the vasodilation to larger vessels upstream, which helps promote the delivery of blood to the exercising muscle.
Organ blood flow responses caused by local mechanisms: active and reactive hyperemias.
In this case, the higher-than-normal blood flow occurs transiently after the removal of any restriction that has caused a period of lower-than-normal blood flow and is sometimes referred to as postocclusion hyperemia. The phenomenon is illustrated in Figure 7–3B. For example, flow through an extremity is higher than normal for a period after a tourniquet is removed from the extremity. Both local metabolic and myogenic mechanisms may be involved in producing reactive hyperemia. The magnitude and duration of reactive hyperemia depend on the duration and severity of the occlusion as well as the metabolic rate of the tissue. These findings are best explained by an interstitial accumulation of metabolic vasodilator substances during the period of flow restriction. However, unexpectedly large flow increases can follow arterial occlusions lasting only 1 or 2 s. These may be explained best by a myogenic dilation response to the reduced intravascular pressure and decreased stretch of the arteriolar walls that exists during the period of occlusion.
Except when displaying active and reactive hyperemia, nearly all organs tend to keep their blood flow constant despite variations in arterial pressure—that is, they autoregulate their blood flow. As shown in Figure 7–4A, an abrupt increase in arterial pressure is normally accompanied by an initial abrupt increase in organ blood flow that then gradually returns toward normal despite the sustained elevation in arterial pressure. The initial rise in flow with increased pressure is expected from the basic flow equation (Q̇ = ΔP/R). The subsequent return of flow toward the normal level is caused by a gradual increase in active arteriolar tone and resistance to blood flow. Ultimately, a new steady state is reached with only slightly elevated blood flow because the increased driving pressure is counteracted by a higher-than-normal vascular resistance. As with the phenomenon of reactive hyperemia, blood flow autoregulation may be caused by both local metabolic feedback mechanisms and myogenic mechanisms. The arteriolar vasoconstriction responsible for the autoregulatory response shown in Figure 7–4A, for example, may be partially due to (1) a “washout” of metabolic vasodilator factors from the interstitium by the excessive initial blood flow and (2) a myogenic increase in arteriolar tone stimulated by the increase in stretching forces that the increase in pressure imposes on the vessel walls. There is also a tissue pressure hypothesis of blood flow autoregulation for which it is assumed that an abrupt increase in arterial pressure causes transcapillary fluid filtration and thus leads to a gradual increase in interstitial fluid volume and pressure. Presumably the increase in extravascular pressure would cause a decrease in vessel diameter by simple compression. This mechanism might be especially important in organs such as the kidney and brain whose volumes are constrained by external structures.
Autoregulation of organ blood flow.
Although not illustrated in Figure 7–4A, autoregulatory mechanisms operate in the opposite direction in response to a decrease in arterial pressure below the normal value. One important general consequence of local autoregulatory mechanisms is that the steady-state blood flow in many organs tends to remain near the normal value over quite a wide range of arterial pressure. This is illustrated in the graph in Figure 7–4B. As discussed later, the inherent ability of certain organs to maintain adequate blood flow despite lower-than-normal arterial pressure is of considerable importance in situations such as shock from blood loss.
Neural Influences on Arterioles
Sympathetic Vasoconstrictor Nerves
These neural fibers innervate arterioles in all systemic organs and provide by far the most important means of reflex
control of the vasculature. Sympathetic vasoconstrictor nerves are the backbone of the system for controlling total peripheral resistance and are thus essential participants in global cardiovascular tasks such as regulating arterial blood pressure.
Sympathetic vasoconstrictor nerves release norepinephrine from their terminal structures in amounts generally proportional to their action potential frequency. Norepinephrine causes an increase in the tone of arterioles after combining with an α1-adrenergic receptor
on smooth muscle cells. Norepinephrine appears to increase vascular tone primarily by pharmacomechanical means. The mechanism involves G-protein linkage of α-adrenergic receptors to phospholipase C and subsequent Ca2+
release from intracellular stores by the action of the second messenger IP3
, as illustrated on the right side of Figure 7–1
Sympathetic vasoconstrictor nerves normally have a continual or tonic firing activity. This tonic activity of sympathetic vasoconstrictor nerves makes the normal contractile tone of arterioles considerably greater than their basal tone. The additional component of vascular tone is called neurogenic tone. When the firing rate of sympathetic vasoconstrictor nerves is increased above normal, arterioles constrict and cause organ blood flow to fall below normal. Conversely, vasodilation and increased organ blood flow can be caused by sympathetic vasoconstrictor nerves if their normal tonic activity level is reduced. Thus, an organ’s blood flow can either be reduced below normal or be increased above normal by changes in the sympathetic vasoconstrictor fiber firing rate.
Blood vessels, as a general rule, do not receive innervation from the parasympathetic division of the autonomic nervous system. However, parasympathetic vasodilator nerves, which release acetylcholine, are present in the vessels of the brain and the heart, but their influence on arteriolar tone in these organs appears to be inconsequential. Parasympathetic vasodilator nerves are also present in the vessels of the salivary glands, pancreas, and gastric mucosa where they have important influences on secretion and motility. In the external genitalia, they are responsible for the vasodilation of inflow vessels responsible for promoting secretion and erection.
Hormonal Influences on Arterioles
Under normal circumstances, short-term hormonal influences on blood vessels are generally thought to be of minor consequence in comparison to the local metabolic and neural influences. However, it should be emphasized that the understanding of how the cardiovascular system operates in many situations is incomplete. Thus, the hormones discussed in the following sections may play more important roles in cardiovascular regulation than is now appreciated.
During activation of the sympathetic nervous system, the adrenal glands release the catecholamines epinephrine and norepinephrine into the bloodstream. Under normal circumstances, the blood levels of these agents are probably not high enough to cause significant cardiovascular effects. However, circulating catecholamines may have cardiovascular effects in situations (such as vigorous exercise or hemorrhagic shock) that involve high activity of the sympathetic nervous system. In general, the cardiovascular effects of high levels of circulating catecholamines parallel the direct effects of sympathetic activation, which have already been discussed; both epinephrine and norepinephrine can activate cardiac β1-adrenergic receptors to increase the heart rate and myocardial contractility and can activate vascular α-receptors to cause vasoconstriction. Recall that in addition to the α1-receptors that mediate vasoconstriction, arterioles in a few organs also possess β2-adrenergic receptors that mediate vasodilation. Because vascular β2-receptors are more sensitive to epinephrine than are vascular α1-receptors, moderately elevated levels of circulating epinephrine can cause vasodilation, whereas higher levels cause α1-receptor-mediated vasoconstriction. Vascular β2-receptors are not innervated and therefore are not activated by norepinephrine, released from sympathetic vasoconstrictor nerves. The physiological importance of these vascular β2-receptors is unclear because adrenal epinephrine release occurs during periods of increased sympathetic activity when arterioles would simultaneously be undergoing direct neurogenic vasoconstriction. Again, under normal circumstances, circulating catecholamines are not an important factor in cardiovascular regulation.
This polypeptide hormone, also known as antidiuretic hormone (or ADH), plays an important role in extracellular fluid homeostasis and is released into the bloodstream from the posterior pituitary gland in response to low blood volume and/or high extracellular fluid osmolarity. Vasopressin acts on collecting ducts in the kidneys to decrease renal excretion of water. Its role in body fluid balance has some very important indirect influences on cardiovascular function, which is discussed in more detail in Chapter 9
. Vasopressin, however, is also a potent arteriolar vasoconstrictor. Although it is not thought to be significantly involved in normal vascular control, direct vascular constriction from abnormally high levels of vasopressin may be important in the response to certain disturbances such as severe blood loss through hemorrhage.
Angiotensin II is a circulating polypeptide that regulates aldosterone release from the adrenal cortex as part of the system for controlling body’s sodium balance. This system, discussed in greater detail in Chapter 9
, is very important in blood volume regulation. Angiotensin II is also a very potent vasoconstrictor agent. Although it should not be viewed as a normal regulator of arteriolar tone, direct vasoconstriction from angiotensin II seems to be an important component of the general cardiovascular response to severe blood loss. There is also strong evidence suggesting that direct vascular actions of angiotensin II may be involved in intrarenal mechanisms for controlling kidney function. In addition, angiotensin II may be partially responsible for the abnormal vasoconstriction that accompanies many forms of hypertension. Again, it should be emphasized that knowledge of many pathological situations—including hypertension—is incomplete. These situations may well involve vascular influences that are not yet recognized.
3 An important exception to this rule occurs in the pulmonary circulation and is discussed later in this chapter.