Arteriolar Tone and Its Regulation (Local Mechanisms)

July 17, 2015 Cardiology, Physiology and Pathophysiology No comments , , , , , , , , , , , , , , , , ,


I.Arteriolar Tone

A.Basal tone


C.Adrenal Glands


1.Metabolic substances

2.Endothelial cells secretion

3.Other local chemical influences

4.Transmural pressure (myogenic response)

II.Venous Tone

A.Basal tone (little)


C.Adrenal glands

D.Internal pressure (recall deltaV/deltaP = C)

E.External compression (muscle pump)

Because the body's needs are continually changing, the cardiovascular system must continually make adjustments in the diameter of its vessels. The purposes of these vascular change are efficiently distribute the cardiac output among tissues with different current needs (the job of arterioles) and regulate the distribute of blood volume and cardiac filling (the job of veins). So besides central regulatory mechanisms for vascular system (CNS, autonomic nerves system) and hormonal regulatory mechanisms (RAAS/angII and vasopressin, natriuretic hormone, insulin resistance and hyperinsulinemia, circulating catecholamines), there are another vascular regulatory mechanism – peripheral regulatory mechanisms/local mechanisms.

Total peripheral resistance (TPR) is determined by resistances of each primary organs and tissues, whereas resistance of an single organ or tissue region is primarily determined by resistances of arterioles that distribute within this organ or tissue. Therefore, TPR is determined primarily by resistance of arterioles. According to the famous Hagen–Poiseuille equation, resistance to flow is inversely and directly related to the radius of the vessel.

(Note: Q = ΔP/R, and R is resistance of the vessel)

Because resistances of arterioles are so important for TPR and the resultant blood flow (Q), we need to study the characteristics of arteriolar resistance carefully. Vascular tone is a term commonly used to characterize the general contractile state (so the radius of the 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. Because the blood flow through any organ is determined largely by its vascular resistance, which dependent primarily on the diameter of its arterioles, thus an organ's flow is controlled by factors that influence the arteriolar smooth muscle tone.

Arterioles remain in a state of partial constriction even all external influences on them are removed; hence, they are said to have a degree of basal 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. Nevertheless, the arterioles have basal tone, and several factors externally influence it, including local influences, neural influences, and hormonal influences.


The capacity of tissues to regulate their own blood flow is referred to as auto regulation. Most vascular beds have an intrinsic capacity to compensate for moderate changes in perfusion pressure by change in vascular resistance, so that blood flow remains relatively constant. The ability of vascular autoregulation is probably due in part to the intrinsic contractile response of smooth muscle to stretch (myogenic theory of autoregulation). That is, as the perfusion pressure rises, the blood vessels are distended and the vascular smooth muscle fivers that surround the vessels contract, which increases the vascular resistance so that the blood flow remains constant (Q = ΔP/R). At the last section of this thread you can find more detail information for the mechanisms and rationales about vascular autoregulation.

General Mechanisms for Activation of the Vascular Smooth Muscle

The task of the vascular smooth muscle is unique, because to maintain a certain vessel diameter in the face of the continual distending pressure of the blood within it, the vascular smooth muscle must be able to sustain active tension for prolonged periods. Compared with other muscle types, smooth muscle cells have these different characteristics, including:

1.Contract and relax much more slowly;

2.Can change their contractile activity as a result of either action potentials or changes in resting membrane potential;

3.Can change their contractile activity in the absence of any change in membrane potential;

4.Can maintain tension for prolonged periods at low energy cost;


5.Can be activated by stretch.

Local Influences on Basal Tone

Local factors influencing arteriolar basal tone (and the diameter of arterioles) include metabolic influences, endothelial cells, other chemical influences, and transmural pressure.

Metabolic Substances. 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. Exposure to low oxygen, and metabolic substances such as high H+, high K+, high CO2, high osmolarity, and adenosine, cause reduced arteriolar tone and vasodilation. By contrary, exposure to high oxygen and low metabolic substances induce increased arteriolar tone and vasoconstriction. When metabolic activity is over the blood supply, oxygen pressure in that tissue gets lower and the metabolic wastes accumulate in the tissue, which cause vasodilation of arterioles. As a result of arteriolar vasodilation, the blood supply to that tissue is improved and oxygen pressure gets back to normal or even higher, whereas increased amount of metabolic wastes are washed away by the improved blood flow therefore the accumulation of metabolic wastes is resolved. Finally, the basal tone gets back to normal.

Endothelial cells cover the entire inner surface of the cardiovascular system. A large number of studies have shown that the blood vessels respond very differently to certain vascular influences when their endothelial lining is missing. 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+. And 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.

Acetylcholine and several other agents such as bradykinin, vasoactive intestinal peptide, and substance P stimulate endothelial cell nitric oxide production because their receipts 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.

One general unresolved issue with the concept that arteriolar tone 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. 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 are a group of several chemically related products of the cyclooxyrgenase pathways of arachidonic acid metabolism, which have vasoactive effects. Certain prostaglandins are potent vasodilators, while some are potent vasoconstrictors. However, despite the vasoactive potency of the prostaglandin and the fact that most tissues are capable of synthesizing prostaglandins, it has not been demonstrated convincingly that prostaglandins play a crucial role in the normal vascular control.

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 (by causing separations in the junctions between the endothelial cells that line the vascular system), which leads to edema formation and local tissue swelling. Other effects that histamine plays include stimulation of sensory nerve endings to produce itching and pain sensation.

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 substances by the action of an enzyme, kvllikrein, and is subsequently rapidly degraded into inactive fragments by various tissue kinases.

Transmural pressure. 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 increases in the internal pressure within an arteriole produces: 1.first an initial slight passive mechanical distention, 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.

Examples of Local Regulation

Active Hyperemia – 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. Active hyperemia could be explained by mechanisms related to local metabolic theory and to local flow-related shear stresses theory.Screen Shot 2015-07-17 at 8.11.32 PM

Reactive Hyperemia – 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 post occlusion 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.

Autoregulation talks about the arterioles' reaction to the changes of the perfusion pressure. 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. For example, 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 later autoregulation that returns the 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. The mechanisms for autoregulation are believed to be both local metabolic feedback theory and myogenic theory. Also, tissue pressure hypothesis of blood flow auto regulation 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.


The Autoregulation of Renal Blood Flow

June 4, 2014 Physiology and Pathophysiology 1 comment , ,

Part I

The capacity of tissues to regulate their own blood flow is referred to as autoregulation. Most vascular beds have an intrinsic capacity to compensate for moderate changes in perfusion pressure by changes in vascular resistance, so that blood flow remains relative constant. This capacity is well developed in the kidneys (see Part II), but it has also been observed in the mesentery, skeletal muscle, brain, liver, and myocardium.

The intrinsic capacity of autoregulation is probably due to in part to the intrinsic contractile response of smooth muscle to stretch (myogenic theory of autoregulation). As the pressure rises, the blood vessels are distended and the vascular smooth muscle fibres that surround the vessels contract. If it is postulated that the muscle responds to the tension in the vessel wall, this theory could explain the greater degree of contraction at higher pressures; the wall tension is proportional to the distending pressure times the radius of the vessel (law of Laplace), and the maintenance of a given wall tension as the pressure rises would require a decrease in radius.

Second, vasodilator substances tend to accumulate in active tissues, and these “metabolites” also contribute to autoregulation (metabolic theory autoregualtion). When blood flow decreases, they accumulate and the vessels dilate; when blood flow increases, they tend to be washed away.

Figure 1 Law of Laplace

Part II

To understand the autoregulation of renal blood flow, firstly, we need to know the normal blood vessels, the innervation of the renal vessels, and the normal renal circulation.

Renal Blood Vessels and Renal Circulation

Renal blood vessels

The renal circulation is diagrammed in Figure 37-3. The afferent arterioles are short, straight branches of the interlobular arteries. Each divides into multiple capillary branches to form the tuft of vessels in the glomerulus. The capillaries coalesce to form the efferent arteriole, which in turn breaks up into capillaries that supply the tubules (peritubular capillaries) before draining into the interlobular veins. There is relatively little smooth muscle in the efferent arterioles.

PS: the arterial segments between glomeruli and tubules are technically a portal system.

The capillaries draining the tubules of the cortical nephrons form a  peritubular network, whereas the efferent arterioles from the juxtamedullary glomeruli drain not only into peritubular network, but also into vessels that form hairpin loops (the vasa recta). These loops dip into the medullary pyramids alongside the loops of Henle. The descending vasa recta have a nonfenestrated endothelium that contains a facilitated transporter for urea, and the ascending vasa recta have a fenestrated endothelium, consistent with their function in conserving solutes.

The efferent arteriole from each glomerulus breaks up into capillaries that supply a number of different nephrons. Thus, the tubule of each nephron dose not necessarily receive blood solely from the efferent arteriole of the same nephron. In humans, the total surface of the renal capillaries is approximately equal to the total surface area of the tubules, both being about 12 m2. The volume of blood in the renal capillaries at any given time is 30-40 mL.

In normal status, the renal blood flow per minute is approximately 1273 mL/min.

Screen Shot 2015-01-08 at 6.44.31 PM

The macula, the neighbouring lacks cells, and the renin-secreting granular cells in the afferent arteriole form the juxtaglomerular apparatus.

Autoregulation of Renal Blood Flow

Function of the renal nerves

Stimulation of the renal nerves increases renin secretion by a direct action of released norepinephrine on β1-adrenergic receptors on the juxtaglomerular cells and it increases Na+ reabsorption, probably by a direct action of norepinephrine on renal tubular cells. The proximal and distal tubules and the thick ascending limb of the loop of Henle are richly innervated (more accurately, the blood vessels of the proximal and distal tubules). When the renal nerves are stimulated to increasing extents in experimental animals, the first response is an increase in the sensitivity of the granular cells in the juxtaglomerular apparatus, followed by increased renin secretion, then increased Na+ reabsorption, and finally, at the highest threshold, renal vasoconstriction with decreased glomerular filtration and renal blood flow. It is still unsettled whether the effect on Na+ reabsorption is mediated via α- or β-adrenergic receptors, and it may be mediated by both. The physiologic role of the renal nerves in Na+ homeostasis is also unsettled, in part because most renal functions appears to be normal in patients with transplanted kidneys, and it takes some time for transplanted kidneys to acquire a functional innervation.

The factors affecting rennin secretion is at thread here .Generally, the stimulation of the renal nerves causes: 1. increased rennin secretion;2. increased Na+ reabsorption;3. renal vasoconstriction;and 4. decreased renal blood flow and GFR.

Regulation of the renal blood flow

Norepinephrine constricts the renal vessels, with the greatest effect of injected norepinephrine being exerted on the interlobular arteries and the afferent arterioles. Dopamine is made in the kidney and causes renal vasodilation and natriuresis (however, controlled trials of dopamine have failed to show a protective effect on renal function). AngII exerts a constrictor effect on both the afferent and efferent arterioles (AngII can try to maintain GFR by constricting the efferent arterioles [when efferent arteriolar constriction is greater than afferent constriction]). Prostaglandins increase blood flow in the renal cortex and decrease blood flow in the renal medulla. Acetylcholine also produces renal vasodilation. A high-protein diet raises glomerular capillary pressure and increase renal blood flow.

Autoregulation of renal blood flow

When the kidney is perfused at moderate pressures (90-220 mm Hg in the dog), the renal vascular resistance varies with the pressure so that renal blood flow is relatively constant (see figure below).

Autoregulation of this type occurs in other organs, and several factors contribute to it (for detail about autoregulation please see the comment after this post). Renal autoregulation is present in denervated and in isolated, perfused kidneys, but is prevented by the administration of drugs that paralyze vascular smooth muscle. It is probably produced in part by a direct contractile response to stretch of the smooth muscle of the afferent arteriole. NO may also be involved.

The main function of the renal cortex is filtration of large volumes of blood through the glomeruli, so it is not surprising that the renal cortical blood flow is relatively great and little oxygen is extracted from the blood (see Table 3.1 below). However, metabolic work is being done, particularly to reabsorb Na+ in the thick ascending limb of Henle, so relative large amounts of O2 are extracted from the blood in the medulla (The PO2 of the cortex is about 50 mm Hg, whereas in medulla it is about 15 mm Hg). I think the reason for the relative high extracting rate includes both relative low blood flow in the medulla and the load of metabolic work. Thus, this makes the medulla vulnerable to hypoxia if flow is reduced further. NO, prostaglandins, and many cardiovascular peptides in this region function in a paracrine fashion to maintain the balance between low blood flow and metabolic needs.

PS: Oxygen Extracted from Various Organs While The Body is at Rest.

Extracted O2 as Percentage of O2 Available