A. General Feature: Intrinsic & Extrinsic Control
B. Intrinsic (local) Control of Peripheral Blood Flow
1. Autoregulation of blood flow
2. Endothelium-dependent flow-mediated vasodilation
3. Reactive hyperemia
4. Functional (active) hyperemia
C. Extrinsic Control of Peripheral Blood Flow
1. Central Nervous System
2. Autonomic Nervous System
Blood flow can be controlled by the local
environment (Δ in pressure, flow, metabolism).
Hormones--affect intrinsic and extrinsic
Extrinsic Control: Blood flow can be controlled by the nervous system (autonomic nervous system and central nervous system).
Effector: Resistance Vessels (arterioles < 100 μm)
Basal tone: constriction adn dilation
Basal tone: tonic activity of smooth muscle independent of innervation.
Influences of arteriolar tone: reflex influence--sympathetic constrictor nerves. Local influences--basal tone and vasodilator metabolites
Autoregulation and Resistance
The intrinsic ability of an organ/tissue to maintain its blood flow nearly constant
despite the changes in perfusion pressure (heart, kidney, brain, & skeletal muscle).
Myogenic mechanism suggests that vascular smooth muscle
contracts when it is stretched (e.g., increased arterial pressure).
• Laplace's law: T = ΔP x r
Metabolic mechanism suggests that the tissue/organ blood flow is determined by the interstitial level of vasodilator metabolites (O2, adenosine, CO2, H+, and K+)
decreased O2 (hypoxia)
increased - adenosine, CO2, H+, and K+
Intrinsic Control of Peripheral Blood Flow:
Endothelium-Dependent Flow-Mediated Vasodilation
Endothelial cells can contribute to the local blood flow regulation by releasing nitric
oxide, which causes vasodilation, in response to an increase in flow or shear stress
• Flow (shear stress)-mediated vasodilation:
Shear stress (tau)=4 n (eta) Q/pir^3
Reactive hyperemia is a phenomenon of increased flow in response to the release of an arterial occlusion.
Reactive hyperemia is dependent upon the duration of blood flow occlusion.
1. Metabolic Response
2. Flow-Mediated Response
Functional (or active) hyperemia is a phenomenon of increased flow in response to the increase of tissue activity.
1. Metabolic Response
2. Flow-Mediated Response
Extrinsic Control of Peripheral Blood Flow
1.Central Nervous System: controls autonomic regulation of cardiovascular function through 3 regions:
a) Medulla: cardiovascular center is located in the reticular formation (RF) of the brain stem.
• cell bodies for sympathetic fibers (pressor area)
• cell bodies for parasympathetic fibers (depressor area)
b) Hypothalamus: temperature control - skin; exercise
c) Cortex: during times of emotional stress (fear and anxiety)
2. Autonomic Nervous System
a) Sympathetic Nervous System:
Preganglionic fibers: Acetylcholine Postganglionic fibers: Norepinephrine Receptors in CV system: i) a adrenergic receptor: vasoconstriction (arterioles & veins) ii) b1 adrenergic receptor:
• in myocardium
• positive inotropic and chronotropic effect iii) b2 adrenergic receptor:
• in vessels
2. Autonomic Nervous System
b) Parasympathetic Nervous System:
Preganglionic fibers: Acetylcholine Postganglionic fibers: Acetylcholine Receptors in CV system: Muscarinic receptors:
• in SA and AV nodes
• in blood vessels of some organs -nitric oxide-mediated dilation & smooth muscle relaxation
The peripheral circulation is essentially under dual control, centrally through the nervous system and locally (or intrinsically) in the tissue by the environmental conditions in the immediate vicinity of the blood vessels. The hormones released in the circulation also can influence the relative importance of these 2 control mechanisms, but it can vary from tissue to tissue. In some areas of the body, such as the skin and the splanchnic (internal organs) regions, neural regulation of blood flow predominates, whereas in others, such as the brain and heart (metabolic regulation more important), this mechanism plays a minor role.
The vessels predominantly involved in regulating the blood flow throughout the body are called the resistance vessels (i.e., arterioles; usually less than 100 μm in most vascular beds). These vessels offer the greatest resistance to the flow of blood pumped to the tissue by the heart and thereby are important in the maintenance of arterial blood pressure. Smooth muscle fibers constitute a large percentage of the composition of the wall of the resistance vessels. Therefore, the vessel lumen can be reduced or increased by contraction or relaxation of the smooth muscle, respectively. Partial contraction (tone) of the vascular smooth muscle exists in the arterioles; therefore, it provides "room" for vasodilation. The resting diameter of arterioles can be influenced by intrinsic basal (myogenic) tone (independent of innervation) and/or neural activation (usually sympathetic nerves). The contribution of these 2 factors to arteriolar tone regulation can vary in different tissues.
Vascular smooth muscle is the tissue responsible for the control of total peripheral resistance, arterial and venous tone, and the distribution of blood flow throughout the body. They are generally arranged in helical or circular layers around the larger blood vessels and in single circular layer around arterioles. Note: endothelial cells are able to release chemicals, such as nitric oxide and prostaglandins, that can alter the vessel diameter, but the vascular smooth cell is the ultimate effector that relaxes (vessel dilation) or constricts to determine the magnitude of vascular tone.
Intrinsic (local) control of peripheral blood flow
In a number of different tissues, the blood flow appears to be adjusted to the existing metabolic activity of the tissue despite the changes in perfusion pressure (arterial blood pressure), which helps avoid a waste of perfusion in organs in which the flow is already sufficient. This phenomenon is called autoregulation: vascular beds in organs/tissues have the ability to adjust their vascular resistance and maintain a relatively constant blood flow in the presence of changes in arterial perfusion pressure. The response occurs locally within the tissue independent of neural and endocrine mechanisms. The autoregulation of skeletal muscle circulation is illustrated in Figure 1. From a control pressure of 100 mmHg (Point A), the pressure is abruptly increased (Point B) or decreased (Point D), and the blood flows observed immediately after changing the perfusion pressure are represented by the closed circles. Maintenance of the altered pressure at each level is followed within 30 or 60 seconds by a return of flow to or toward the control levels; the open circles represent these steady-state flows. Over the pressure range of 20 to 120 mmHg, the steady-state flow is relatively constant. Calculation of the resistance across the vascular bed (perfusion pressure or ΔP / blood flow) during steadystate conditions indicates that with elevation of perfusion pressure the resistance vessels constrict (to increase resistance, Point C), whereas with reduction of perfusion pressure, they dilate (to reduce resistance, Point E). Autoregulation is well developed in the kidney, brain (cerebral), heart (coronary), and skeletal muscle; the autoregulatory range of perfusion pressure for each of these organs varies. The mechanism responsible for the autoregulation of blood flow is not known, but it appears to be explained best by the following two hypotheses (myogenic and metabolic hypotheses).
The myogenic mechanism suggests that vascular smooth muscle of arterioles contracts (by increasing its intracellular calcium) when it is stretched, which would occur when blood pressure inside the vessel increases. Vascular smooth muscle responds to wall tension, which is a function of pressure and radius of the vessel wall, according to Laplace's law. Therefore, an increase in arterial pressure raises wall tension, initially stretching the smooth muscle fibers. In response to the initial
stretch, the vascular smooth muscle contracts, returning wall tension to the control
level. The narrowed lumen now represents an increased resistance and compensates
for the increased arterial pressure, returning blood flow to the control level. On the
other hand, when arterial perfusion pressure suddenly decreases there is less stretch
(tension) on the arterioles and the vessels relax leading to decreased resistance and
return of normal flow. The myogenic response (i.e., vasoconstriction in response to elevation of luminal pressure) recorded from an isolated coronary arteriole in vitro is
shown in Figure 2.
Smooth muscle cells in the arteriolar wall are exposed to the chemical composition of the interstitial fluid of the organ they serve. Interstitial concentrations of many substances reflect the balance between the metabolic activity of the tissue and its blood supply. Interstitial O2 levels, for example, fall whenever the tissue cells are utilizing O2 faster than it is being supplied to the tissue by blood flow. Conversely, interstitial O2 levels rise whenever excess O2 is being delivered to a tissue from the blood. Whenever blood flow and oxygen delivery fall below a tissue's O2 demand, the O2 levels around arterioles fall, the arterioles dilate, and the blood flow through the organ appropriately increases. Many substances in addition to O2 are present within tissues and can affect the tone of vascular smooth muscle. When the metabolic rate of skeletal muscle is increased by exercise, for example, not only does the tissue level of O2 decrease, but also the levels of CO2, H+, lactate, and K+ increase. Muscle tissue osmolarity also increases during exercise. All of these chemical alterations cause arteriolar dilation. In addition, with increased metabolic activity or oxygen deprivation, cells in many tissues may release adenosine (metabolite from ATP breakdown), which is an extremely potent vasodilator agent. Several factors may be involved in any given vascular bed, and different factors play significant roles in different tissues.
For conceptual purpose, our understanding of local metabolite control can be summarized as shown in Figure 3. Vasodilator factors enter the interstitial space of the tissue cells at a rate proportional to tissue metabolism. These vasodilators 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 concentrations will build up and cause the arterioles to dilate and thus subsequently increase blood flow. This process will continue until the metabolic demand is matched by the increased blood flow. 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 levels of metabolic vasodilators. With this in mind, the flow autoregulation phenomenon can be readily explained. For example, an increase in arterial blood pressure (increased perfusion pressure) will initially increase blood flow to a tissue or organ. This increased blood flow will "wash out" vasodilator substances in the area, and thus vascular resistance increases (arterioles now have decreased radius and increased tone) and blood flow returns to the normal resting level (Figure 3).
Endothelium dependent regulation of blood flow (endothelium-dependent flow mediated vasodilation)
As described in the Microcirculation lecture (Figure 3), endothelial cells can contribute to the local blood flow regulation through the release of vasoactive substances. In addition to the activation of endothelium by pharmacological/chemical agents, the endothelium can release nitric oxide in response to an increase in wall shear stress (τ) caused by the increased flow (Q) - this is a parallel force acting on the vessel endothelium. The following equation describes their relationship:
τ = 4 η Q / πr3, where
η = viscosity of fluid, and r = radius of vessel
Under these conditions the increased flow will initiate an increase in wall shear stress. However, the vessels will tend to keep shear stress constant by increasing vessel radius (vasodilation). If shear stress is too high for a long period of time this can damage the endothelial cells and lead to vascular dysfunction, so this phenomenon helps maintain relatively constant shear stress. Important Note: This is not a mechanism for
autoregulation of blood flow, since in this case, an increase in flow/shear stress promotes arteriolar dilation, which can further increase flow (flow-induced vasodilation). Instead, this vascular regulatory mechanism may play a role in local blood flow control during reactive and functional hyperemia as described below. Figure 4 shows an example of flow-induced vasodilation of an isolated coronary arteriole in vitro.
If arterial inflow to a vascular bed is stopped for a few seconds to several minutes, the blood flow, on release of the occlusion, immediately exceeds the flow before occlusion and then gradually returns to the control level. This phenomenon is termed "reactive hyperemia" and is illustrated in Figure 5.
The magnitude of reactive hyperemia is dependent upon the duration of blood flow occlusion. This time-dependent response is illustrated in Figure 6, which shows that blood flow to the skeletal muscle was stopped by clamping the femoral artery for 15, 30, and 60 seconds. Release of the 60-second occlusion resulted in a peak blood flow 70% greater than the control flow, with a return to control flow within about 110 seconds. Note that the peak flow and duration of the reactive hyperemia are proportional to the duration of the occlusion. During arterial (large artery upstream from arterioles) occlusion, the blood flow is stopped and downstream arteriolar pressure is reduced. These changes would elicit metabolic (increased metabolites due to lack of flow) dilation of resistance vessels. At the moment of releasing the occlusion, the flow would suddenly increase due to the reduction of arteriolar resistance (e.g., vasodilation). The increased flow would trigger the vessels to further dilate (flow-mediated vasodilation - see below). However, these vasodilator responses are gradually diminished due to the replenishment of nutrients and washing out of metabolic vasodilators by the increased flow. Flowmediated dilation is also diminished with a gradual return of blood flow toward control.
Functional (active) Hyperemia
Functional (or active) hyperemia is defined as the increase in blood flow caused by enhanced tissue metabolic activity (e.g., strenuous exercise - increased blood flow to heart and skeletal muscle) as shown in Figure 7.
For functional hyperemia, the metabolic and flow-mediated vasodilator mechanisms might be responsible for the observed increase in blood flow during metabolic activation. The metabolic control exerts a dominant effect on the small arterioles. In contrast, the large arterioles or small arteries that feed the small arterioles are responsive to shear stress changes (flow-mediated vasodilation mechanism). If metabolic demand of the tissue is increased, it is expected that small downstream arterioles preferentially dilate, presumably as a result of increased production of metabolic vasodilators. Metabolic dilation of distal arterioles would lower intraluminal pressure and vascular resistance in the upstream feeder arteries leading to accelerated blood flow in these vessels and initiation of flow-induced dilation. Thus, metabolic dilation of small arterioles can potentially recruit dilation of upstream arterioles via a flow-mediated mechanism, which would serve to lessen overall resistance and improve O2 delivery to the active tissue.
Extrinsic Control of Peripheral Blood Flow
1. Central Nervous System (CNS)
a. Medulla: Diffuse collection of cells involved in the integration of cardiovascular function is located within the reticular formation of the brain stem.
i. Pressor and depressor areas are located in the dorsal-lateral and ventro-medial portion of the reticular formation, respectively. The depressor response results from the withdrawal of vasoconstrictor influences (e.g., inhibition of the medullary pressor region), rather than an active vasodilation.
ii. The cardiovascular and cardiopulmonary centers are also located in the reticular formation. These centers send impulses to the heart over the cardiac sympathetic and vagal nerves, respectively.
b. Hypothalamus: The medullary cardiovascular centers can receive input from higher levels of the brainstem (hypothalamus).
i. The effects of temperature changes on the hypothalamic centers are relayed to the medulla, which causes the vessels of the skin to constrict (to conserve heat; will be discussed in detail during Regional Circulation lecture) or to dilate (to dissipate heat).
ii. Emotional stress can influence heart rate and blood pressure. These effects are relayed from the higher centers to stimulate or inhibit the medullary centers.
c. Cortex: Stimulation of various areas of the motor cortex leads to complex motor responses that include appropriate cardiovascular adjustments. These complex motor patterns involve autonomic responses.
Automatic Nervous System
a. Sympathetic Nervous System: Most of the sympathetic nerves to blood vessels exhibit some neural activity that induces some degree of vasoconstriction. Thus, increasing or decreasing the sympathetic neural activity can produce vasoconstriction (increase vessel tone) or vasodilation (decrease vessel tone).
i. Innervation: The heart and circulation are supplied by sympathetic fibers. All of the preganglionic sympathetic fibers are cholinergic (acetylcholine is the neurotransmitter), but postganglionic sympathetic fibers are primarily adrenergic (norepinephrine is the neurotransmitter) (Figure 8).
ii. Receptors: The sympathetic nervous system contains α and ß receptors. In the cardiovascular system, the α and ß receptors have the following effects:
α Receptors are stimulated most strongly by norepinephrine, which causes vasoconstriction. Arteriolar constriction causes an increase in arterial pressure and reduces local blood flow. Venoconstriction can significantly decrease compliance of veins and shift blood toward the heart, thus aiding venous return to the right side of the heart.
ß Receptors are strongly stimulated by isoproterenol and epinephrine, but only slightly respond to norepinephrine. There are two major ß receptor subtypes. The ß1 receptors are located in the myocardium (not the coronary arteries); activation of these receptors results in positive (increased) inoptropic (force of heart muscle contraction) and chronotropic (rate of heart contraction - heart beat) responses (these terms will be explained in detail in subsequent lectures on the heart). The ß2 receptors are located in arteries/arterioles; activation of these receptors leads to vasodilation.
b. Parasympathetic Nervous System: This nervous system arises from the cranial and sacral outflow of the CNS (Figure 9). The primary effect of the parasympathetic system on cardiovascular function is to slow the heart rate. Impulses conducted by the vagus nerve affect the sinoatrial (SA) and atrioventricular (AV) nodes and directly reduce atrial contractility. The efferent
fibers of the cranial division of the parasympathetic nervous system supply blood vessels of the head and viscera, whereas fibers of the sacral division supply blood vessels of the genitalia, bladder, and large bowel. Skeletal muscle and skin do not receive parasympathetic innervation. Because only a small proportion of the resistance vessels of the body receive parasympathetic fibers, the effect of these
cholinergic fibers on total vascular resistance is small. The neurotransmitter released from the postganglionic cholinergic fibers is acetylcholine, which acts on the muscarinic (cholinergic) receptors. Acetylcholine causes endothelial release of nitric oxide leading to smooth muscle relaxation and dilation.