Renal Blood Flow

[Physiology] Vascular Control in Specific Organs

June 2, 2016 Cardiology, Critical Care, Hemodynamics, Physiology and Pathophysiology, Pulmonary Medicine No comments , , , , , , , , , , , , , , , , , , , , , , , , ,

In General

Basal tone, local metabolic vasodilator factors, and sympathetic vasoconstrictor nerves acting through alpha1-receptors are the major factors controlling arteriolar tone and therefore the blood flow rate through peripheral organs. Sympathetic vasoconstrictor nerves, internal pressure, and external compressional forces are the most important influences on venous diameter and therefore on peripheral-central distribution of blood volume. Compared with arterioles, veins normally have little basal tone. Thus, veins are normally in a dilated state. One important consequence of the lack of basal venous tone is that vasodilator metabolites that may accumulate in the tissue have little effect on vein.

  • Arteriolar Tone

    • Basal tone
    • ANS
    • Adrenal Glands
    • Local

      • Metabolic substances
      • Endothelial cells secretion
      • Other local chemical influences
      • Transmural pressure (myogenic response)
  • Venous Tone

    • Basal tone (little)
    • ANS
    • Adrenal glands
    • Internal pressure (recall deltaV/deltaP = C)
    • External compression

Coronary Blood Flow

  • 4% of cardiac output (at rest)
  • Vasodilation – local metabolic mechanisms (to outweight sympathetic vasoconstriction)
  • Systolic compression (left ventricle)
  • Local O2ER 70-75% (at rest)

The major right and left coronary arteries that serve the heart tissue are the first vessels to branch off the aorta. Thus, the driving force for myocardial blood flow is the systemic arterial pressure, just as it is for other systemic organs. Most of the blood that flows through the myocardial tissue returns to the right atrium by way of a large cardiac vein called the coronary sinus.

Coronary blood flow is controlled primarily by local metabolic mechanisms. It responds rapidly and accurately to changes in myocardial oxygen consumption. The issue of which metabolic vasodilator factors play the dominant role in modulating the tone of coronary arterioles is unresolved at present. Many suspect that adenosine, released from myocardial muscle cells in response to increased metabolic rate, may be an important coronary metabolic vasodilator influence. Regardless of the specific details, myocardial oxygen consumption is the most important influence on coronary blood flow.

In a resting individual, the myocardium extracts 70% to 75% of the oxygen in the blood that passes through it. Because of this high extraction rate, coronary sinus blood normally has a lower oxygen content than blood at any other place in the cardiovascular system. Because myocardial oxygen extraction cannot increase significantly from its high resting value, increases in myocardial oxygen consumption must be accompanied by appropriate increases in coronary blood flow.

Large forces and/or pressures are generated within the myocardial tissue during cardiac muscle contraction. Such intramyocardial forces press on the outside of coronary vessels and cause them to collapse during systole. Because of this systolic compression and the associated collapse of coronary vessels, coronary vascular resistance is greatly increased during systole. The result, at least for much of the left ventricular myocardium, is that coronary flow is lower during systole than during diastole, even though systemic arterial pressure (i.e., coronary perfusion pressure) is highest during systole. Systolic compression has much less effect on flow through the right ventricular myocardium. This is because the peak systolic intraventricular pressure is much lower for the right heart than for the left heart, and the systolic compressional forces in the right ventricular wall are correspondinly less than those in the left ventricular wall.

Systolic compressional forces on coronary vessels are greater in the endocardial layers of the left ventricular wall than in the epicardial layers. Thus, the flow to the endocardial layers of the left ventricle is impeded more than the flow to the epicardial layers by systolic compression. Normally, the endocardial region of the myocardium can make up for the lack of flow during systole by a high flow in the diastolic interval. However, when coronary blood flow is limited the endocardial layers of the left ventricle are often the first regions of the heart to have difficulty maintaining a flow sufficient for their metabolic needs.

Coronary arterioles are densely innervated with sympathetic vasoconstrictor fibers, yet when the activity of the sympathetic nervous system increases, the coronary arterioles normally vasodilate rather than vasoconstrict. This is because an increase in sympathetic tone increases myocardial oxygen consumption by increasing the heart rate and contractility. The increased local metabolic vasodilator influence apparently outweighs the concurrent vasoconstrictor influence of an increase in the activity of sympathetic vasoconstrictor fibers that terminate on coronary arterioles.


Skeletal Muscle Blood Flow

  • Important to overall cardiovascular hemodynamics (large mass; sympathetic vasoconstriction only has impact for cardiac output, not for blood volume [due to sparsely innervated with sympathetic vasoconstrictor fibers])
  • Vasodilation – local metabolic mechanisms (countered by sympathetic vasoconstriction to prevent over-vasodilation which might result in not enough cardiac output to maintain arterial pressure)
  • Skeletal muscle pump – enhance venous return
  • 15% of the cardiac output (at rest)
  • Local O2ER 25-30% (at rest)

Because of the large mass of the skeletal muscle, blood flow through it is an important factor in overall cardiovascular hemodynamics. Collectively, the skeletal muscles constitute 40% to 45% of body weight – more than any other single body organ. Even at rest, approximately 15% of the cardiac output goes to skeletal muscle, and during strenuous exercise, the skeletal muscle may receive more than 80% of the cardiac output.

Resting skeletal muscle has a high level of intrinsic vascular tone. Because of this high tone of the smooth muscle in resistance vessels of resting skeletal muscle, the blood flow per gram of tissue is quite low when compared with that of other organs. However, resting skeletal muscle blood flow is still substantially above that required to sustain its metabolic needs. Resting skeletal muscles normally extract only 25% to 30% of the oxygen delivered to them in arterial blood. Thus, changes in the activity of sympathetic vasoconstrictor fibers can reduce resting muscle blood flow without compromising resting tissue metabolic processes.

Local metabolic control of arteriolar tone is the most important influence on blood flow through exercising muscle. A particular important characteristic of skeletal muscle is its very wide range of metabolic rates. During heavy exercise, the oxygen consumption rate of and oxygen extraction by skeletal muscle tissue can reach the high values typical of the myocardium (70-75%). In most respects, the factors that control blood flow to exercising muscle are similar to those that control coronary blood flow (metabolic mechanisms). Local metabolic control of arteriolar tone is very strong in exercising skeletal muscle, and muscle oxygen consumption is the most important determinant of its blood flow.

Alterations in sympathetic neural activity can alter nonexercising skeletal muscle blood flow. For example, maximum sympathetic discharge rates can decrease blood flow in a resting muscle to less than one fourth its normal value, and conversely, if all neurogenic tone is removed, resting skeletal muscle blood flow may double. This is a modest increase in flow compared with what can occur in an exercising skeletal muscle. Nonetheless, because of the large mass of issue involved, changes in the vascular resistance of resting skeletal muscle brought about by changes in sympathetic activity are very important in the overall reflex regulation of arterial pressure. In exercising muscles, the increased sympathetic vasoconstrictor nerve acivity is not evident as outright vasoconstriction but does limit the degree of metabolic vasodilation, which seemingly is a counterproductive process that serves to prevent an excessive reduction in total peripheral resistance during exercise (over-vasodilation). This process is of very importance because if arterioles in most of the skeletal muscles in the body were allowed to dilate to their maximum capacity simultaneously, total peripheral resistance would be so low that the heart could not possibly supply enough cardiac output to maintain arterial pressure.

As in the heart, muscle contraction produces large compressional forces within the tissue, which can collapse vessels and impede blood flow. Strong, sustained (tetanic) skeletal muscle contractions may actually stop muscle blood flow. Approximately 10% of the total blood volume is normally contained within the veins of the skeletal muscle, and during rhythmic exercise, the "skeletal muscle pump" is very effective in displacing blood from skeletal muscle veins. Valves in the veins prevent reverse flow back into the muscles. Blood displaced from the skeletal muscle into the central venous pool is an important factor in the hemodynamics of strenuous whole body exercise.

Veins in skeletal muscle can constrict in response to increased sympathetic activity. However, veins in the skeletal muscle are rather sparsely innervated with sympathetic vasoconstrictor fibers, and the rather small volume of blood that can be mobilized from the skeletal muscle by sympathetic nerve activation is probably not of much significance to total body hemodynamics. This is in sharp contrast to the large displacement of blood from exercising muscle by the muscle pump mechanism.


Cerebral Blood Flow

  • Interruption of flow more than a few seconds is dangerous
  • Flow regulated by local mechanisms
  • 12% of cardiac output (at rest)
  • Brain metabolism rate is constant
  • Brain flow starts to fall when arterial BP is under 60 mm Hg
  • ANS's infuence on cerebral blood flow is minimal

Interruption of cerebral blood flow for more than a few seconds leads to unconsciousness and to brain damage within a very short period. One rule of overall cardiovascular system function is that, in all situations, measures are taken that are appropriate to preserve adequate blood flow to the brain.

Cerebral blood flow is regulated almost entirely by local mechanisms (by local metabolites and/or myogenic mechanisms?). The brain as a whole has nearly constant rate of metabolism that, on a per gram basis, is nearly as high as that of myocardial tissue. Flow through the cerebrum is autoregulated very strongly and is little affected by chagnes in arterial pressure unless it falls below approximately 60 mm Hg (brain blood flow starts to decrease below this level).

PS: Local mechanisms include: 1).autoregulation; 2).metabolites; and 3).local vasoconstriction (in the face of artery injuries). Detail: Arteriolar Tone and Its Regulation (local mechanisms) http://www.tomhsiung.com/wordpress/2015/07/arteriolar-tone-and-its-regulation-local-mechanisms/

Sympathetic and parasympathetic neural influences on cerebral blood flow are minimal. Although cerebral vessels receive both sympathetic vasoconstrictor and parasympathetic vasodilator fiber innervation, cerebral blood flow is influenced very little by changes in the activity of either under normal circumstances. Sympathetic vasoconstrictor responses may, however, be important in protecting cerebral vessels from excessive passive distention following large, abrupt increases in arterial pressure.

The "blood-brain barrier" refers to the tightly connected vascular endothelial cells that severely restrict transcapillary movement of all polar and many other substanes. Because of this blood-brain barrier, the extracellular space of the brain represents a special fluid compartment in which the chemical composition is regulated separately from that in the plasma and general body extracellular fluid compartment. The extracellular compartment of the brain encompasses both interstitial fluid and cerebrospinal fluid (CSF), which surround the brain and the spinal cord and fills the brain ventricles. These processes regulate the chemical composition of the CSF. The interstitial fluid of the brain takes on the chemical composition of CSF through free diffusional exchange. The blood-brain barrier serves to protect the cerebral cells from ionic disturbances in the plasma. Also, by exclusion and/or endothelial cell metabolism, it prevents many circulating hormones (and drugs) from influencing the parenchymal cells of the brain and the vascular smooth muscle in brain vessels.

Although many organs can tolerate some level of edema, edema in the brain represents a crisis situation (increased intracranial pressure). Cerebral edema increases intracranial pressure, which must be promptly relieved to avoid brain damage. Special mechanisms involving various specific ion channels and transporters precisely regualte the transport of solute and water across astrocytes and the endothelial barrier. These mechanisms contribute to normal maintenance of intracellular and extracellular fluid balance.


Splanchnic Blood Flow

  • Splanchnic blood flow has big impact on overall hemodynamics (both blood flow and blood volume)
  • Sympathetic activity has big impacts on splanchnic blood flow and volume
  • 25% of cardiac output (at rest)
  • 20% of circulating blood volume (at rest)
  • Local O2ER 15% to 20% (at rest)

Because of the high blood flow through and the high blood volume in the splanchnic bed, its vascular control importantly influences over all cardiovascular hemodynamics. A number of abdominal organs, including the gastrointestinal tract, spleen, pancreas, and liver, are collectively supplied with what is called the splanchnic blood flow. Splanchnic blood flow is supplied to these abdominal organs through many arteries, but it all ultimately passes through the liver and returns to the inferior vena cava through the hepatic veins. The organs of the splanchnic region receive approximately 25% of the resting cardiac output and contain more than 20% of the circulating blood volume. Thus, adjustments in either the blood flow or the blood volume of this region have extremely important effects on the cardiovascular system.

Sympathetic neural activity plays an important role in vascular control of the splanchnic circulation. Collectively, the splanchnic organs have a relatively high blood flow and extract only 15% to 20% of the oxygen delivered to them in the arterial blood. The arteries and veins of all the organs involved in the splanchnic circulation are richly innervated with sympathetic vasoconstrictor nerves. Maximal activation of sympathetic vasoconstrictor nerves can produce an 80% reduction in flow to the splanchnic region and also cause a large shift of blood from the splanchnic organs to the central venous pool. Humans, a large fraction of the blood mobilized from the splanchnic circulation during periods of sympathetic activation comes from the constriction of veins in the liver.

Local metabolic activity associated wtih gastrointestinal motility, secretion, and absorption is associated with local increases in splanchnic blood flow. There is great diversity of vascular structure and function among indidiviual organs and even regions within organs in the splanchnic region. The mechanisms of vascular control in specific areas of the splanchnic region are not well understood but are likely to be quite varied. Nonetheless, because most splanchnic organs are involved in the digestion and absorption of food from the gastrointestinal tract, overall splanchnic blood flow increases after food ingestion. Parasympathetic neural activity is involved in many of these gastrointestinal functions, so it is indirectly involved in increasing splanchnic blood flow. A large meal can elicit a 30% to 100% increase in splanchnic flow, but individual organs in the splanchnic region probably have higher percentage increases in flow at certain times because they are involved sequentially in the digestion – absoprtion process.


Renal Blood Flow

  • Renal function is itself of paramount important to overall cardiovascular function
  • 20% of cardiac output (at rest)
  • Changes in renal blood volume are of no signifance to overall cardiovascular hemodynamics
  • Sympathetic activity has big impacts on renal blood flow
  • Local metabolic mechanism may influence local vascular tone, but physiological roles are not clear

Renal blood flow plays a critical role in the kidney's main long-term job of regulating the body's water balance and therefore circulating blood volume. However, acute adjustments in renal blood flow also have important short-term hemodynamic consequences. The kidneys normally receive approximately 20% of the cardiac output of a resting individual. This flow can be reduced to practically zero during strong sympathetic activation. Thus, the control of renal blood flow is important to overall cardiovascular function. However, because the kidneys are such small organs, changes in renal blood volume are inconsequential to overall cardiovascular hemodynamics.

Renal blood flow is strongly influenced by sympathetic neural stimulation. Alterations in sympathetic neural activity can have marked effects on total renal blood flow by altering the neurogenic tone of renal resistance vessels. In fact, extreme situations involving intense and prolonged sympathetic vasoconstrictor activity can lead to dramatic reduction in renal blood flow, permanent kidney damage, and renal failure.

Local metabolic mechanism may influence local vascular tone, but physiological roles are not clear. It has long been known that experimentally isolated kidneys (i.e., kidneys deprived of their normal sympathetic input) autoregulate their flow quite strongly (for detail about seek threads THE AUTOREGULATION OF RENAL BLOOD FLOW at http://www.tomhsiung.com/wordpress/2014/06/the-autoregulation-of-renal-blood-flow/ and ARTERIOLAR TONE AND ITS REGULATION (LOCAL MECHANISMS) at http://www.tomhsiung.com/wordpress/2015/07/arteriolar-tone-and-its-regulation-local-mechanisms/). The mechanism responsible for this phenomenon has not been definitely established, but myogenic, tissue pressure, and metabolic hypotheses have been advanced. The real question is what purpose such a strong local mechanism plays in the intact organism where it seems to be largely overridden by reflex mechanisms. In an intact individual, renal blood flow is not constant but is highly variable, depending on the prevailing level of sympathetic vasoconstrictor nerve activity. (For how renal plasma flow affects drug clearance [pharmacokinetics] please see thread PHARMACOKINETICS SERIES – CLEARANCE AND MAINTENANCE DOSE at http://www.tomhsiung.com/wordpress/2015/03/pharmacokinetics-series-clearance-and-maintenance-dose/).

The mechanisms responsible for the intrinsic regulation of renal blood flow and kidney function have not been established. Although studies suggest that prostaglandins and some intrarenal renin-angiotensin system may be involved, the whole issue of local renal vascular  control remains quite obscure. Renal function is itself of paramount important to overall cardiovascular function.


Cutaneous Blood Flow

  • Cutaneous blood flow is related to regulation of body temperature
  • 6% of cardiac output (at rest)
  • Cutaneous blood flow can increases up to 7-fold with vasodilation
  • Venous constriction can shift a considerable volume of blood to central venous pool

The physiological role of skin blood flow is to help regulate body temperature. The metabolic activity of body cells produces heat, which must be lost in order for the body temperature to remain constant. The skin is the primary site of exchange of body heat with the external environment. Alterations in cutaneous blood flow in response to various metabolic states and environmental conditions provide the primary mechanism responsible for temperature homeostasis.

Decreases in body tempeature (core temperature) decrease skin blood flow and vice versa. Cutaneous blood flow, which is approximately 6% of resting cardiac output, can decrease to about one-twentieth of its normal value when heat is to be retained. In contrast, cutaneous blood flow can increase up to seven times its normal value when heat is to be lost.

temperature-regulation-by-skin-27-638Structural adaptations of the cutaneous vascular beds promote heat loss or heat conservation. An extensive system of interconnected veins called the venous plexus normally contains the largest fraction of cutaneous blood volume, which, individuals with hightly pigmented skin, gives the skin a reddish hue. To a large extent, heat transfer from the blood takes place across the large surface area of the venous plexus. The venous plexus is richy innervated with sympathetic vasoconstrictor nerves. When these fibers are activated, blood is displaced from the venous plexus, and this helps reduce heat loss and also lightens the skin color. Because the skin is one of the largest body organs, venous constriction can shift a considerable amount of blood into the central venous pool.

Reflex sympathetic neural activity has important but complex influences on skin blood flow. Cutaneous resistance vessels are richly innervated with sympathetic vasoconstrictor nerves, and because these fibers have a normal tonic activity, cutaneous resistance vessels normally have a high degree of neurogenic tone. When body temperature rises above normal, skin blood flow is increased by reflex mechanisms. In certain areas (such as the hands, ears, and nose), vasodilation appears to result entirely from the withdrawal of sympathetic vasoconstrictor tone. In other areas (such as the forearm, forehead, chin, neck, and chest), the cutaneous vasodilation that occurs with body heating greatly exceeds that which occurs with just the remvoal of sympathetic vasoconstrictor tone. This "active" vasodilation is closely linked to the onset of sweating in these areas. The sweat glands in human cutaneous tissue involved in thermoregulation are innervated by cholinergic sympathetic fibers that release acetylcholine. Activation of these nerves elicits sweating and an associated marked cutaneous vasodilation (see post Responses of Some Effector Organs to Autonomic Nerve Activity at http://forum.tomhsiung.com/pharmacy-research-study-and-policy/physiology-and-pathophysiology/916-responses-of-some-effector-organs-to-autonomic-nerve-activity.html).

Cutaneous vessels respond to changes in local skin temperature. In general, local cooling leads to local vasoconstriction and local heating causes local vasodilation. The mechanisms for this are unknown. If the hand is placed in ice water, there is initially a nearly complete cessation of hand blood flow accompanied by intense pain. After some minutes, hand blood flow begins to rise to reach values greately in excess of the normal value, hand temperature increases, and the pain disappears. This phenomenon is referred to as cold-induced vasodilation. With continued immersion, hand blood flow cycles every few minutes between periods of essentially no flow and periods of hyperemia. The mechanism responsible for cold vasodilation is unknown.

Cutaneous vessels respond to local damage with observable responses. Tissue damage from burns, ultravioler radiation, cold inury, caustic chemicals, and mechanical trauma produces reactions in the skin blood flow. A classical reaction called the triple response is evoked after vigorously stroking the skin with a blunt point. The first component of the triple response is a red line that develops along the direct path of the abrasion in approximately 15 s. Shortly thereafter, an irregular red flare appears that extends approximately 2 cm on either side of the red line. Finally, after a minute or two, a wheal appears along the line of the injury. The mechanisms involved in the triple response are not well understood, but it seems likely that histamine release from damage cells is at least partially responsible for the dilation evidenced by the red line and teh subsequent edema formation of the wheal. The red flare seems to involve nerves in some sort of a local axon reflex, because it can be evoked immediately after cutaneous nerves are sectioned but not after the peripheral portions of the sectioned nerves degenerate.


Pulmonary Blood Flow

  • Pulmonary blood flow equals cardiac ouput
  • Pulmonary veins serve a blood reservoir function for the cardiovascular system
  • Pulmonary vascular resistance is one-seventh of total SVR
  • An increase in pulmonary arterial pressure decrease pulmonary vascular resistance
  • Pulmomary arterioles constrict in response to alveolar hypoxia
  • Autonomic nerves play no major role in control of pulmonary vascular activity

Pulmonary blood flow equals cardiac output. Except for very transient adjustments, the rate of blood flow through the lungs is necessarily equal to cardiac output of the left venticle in all circumstances. When cardiac output to the systemic circulation increases threefold during exercise, for example, pulmonary blood flow must also increase threefold.

Pulmonary vascular resistance is about one-seventh of total systemic vascular resisrance. Pulmonary vessels do offer some vascular resistance. Although the level of pulmonary vascular resistance does not usually influence the pulmonary flow rate, it is important because it is one of the determinants of pulmonary arterial pressure. Recall that mean pulmonary arterial pressure is approximately 13 mm Hg (9-18 mm Hg), whereas mean systemic arterial pressure is approximately 100 mg Hg (70-105 mm Hg). The reason for the difference in pulmonary and systemic arterial pressures is not that the right side of the heart is weaker than the left side of the heart, but rather that pulmonary vascular resistrance is inherently much lower than systemic total peripheral resistance. The pulmonary bed has a low resistance because it has relatively large vessels throughout.

Pulmonary arteries and arterioles are less muscular and more compliant than systemic arteries and arterioles. When pulmonary arterial pressure increases, the pulmonary arteries and arterioles become larger in diameter. Thus, an increase in pulmonary arterial pressure decreases pulmonary resistance. This phenomenon is important because it tends to limit the increase in pulmonary arterial pressure that occurs with increases in cardiac output.

Pulmonary arterioles constrict in response to local alveolar hypoxia. One of the most important and unique active responses in pulmonary vasculature is hypoxic vasoconstriction of pulmonary arterioles in response to low oxygen levels within alveoli (Note: This is a response to alveolar hypoxia, not to low levels of oxygen in the blood – i.e., hypoxemia). This is exactly opposite to the vasodilation that occurs in systemic arterioles in response to low tissue PO2. The mechanisms that cause this unusual response in pulmonary vessels are unclear but seem to be dependent upon oxygen sensing by the pulmonary arterial smooth muscle cells. Current evidence suggests that local endothelin production or prostaglandin synthesis may be involved in pulmonary hypoxic vasoconstriction. Whatever the mechanism, hypoxic vasoconstriction is essential to efficient lung gas exchange because it diverts blood flow away from areas of the lung that are underventilated. Consequently, the best-ventilated areas of the lung also receive the most blood flow. As a consequence of hypoxic arteriolar vasoconstriction, general hypoxia causes an increase in pulmonary vascular resistance and pulmonary arterial hypertension.

Autonomic nerves play no major role in control of pulmonary vascular activity. Both pulmonary arteries and veins receive sympathetic vasoconstrictor fiber innervation, but reflex influences on pulmonary vessels appear to be much less important than the physical and local hypoxic influences. Pulmonary veins serve a blood reservoir function for the cardiovascular system, and sympathetic vasoconstriction of pulmonary veins may be imporant in mobilizing this blood during periods of general cardiovascular stress.

Low capillary hydrostatic pressure promotes fluid reabsorption and prevents fluid accumulation in pulmonary airways. A consequence of the low mean pulmonary arterial pressure is the low pulmonary capillary hydrostatic pressure of approximately 8 mm Hg (compared with approximately 25 mm Hg in systemic capillaries). Because the plasma oncotic pressure in lung capillaries is near 25 mm Hg, as it is in all capillaries, it is likely that the transcapillary forces in the lungs strongly favor continual fluid reabsorption. This cannot be the complete story, however, because the lungs, like other tissues, continually produce some lymph and some net capillary filtration is required to prodcue lymphatic fluid. This filtration is possible despite the unusually low pulmonary capillary hydrostatic pressure because pulmonary interstitial fluid has an unusually high protein concentration and thus oncotic pressure.


Other distribution of cardiac output (blood flow)

5% bone

5% adipose tissue

0.2% adrenal glands

2.5% lung

1.5% thyroid

3.3 others

Reference: https://www.umc.edu/Education/Schools/Medicine/Basic_Science/Physiology_and_Biophysics/Core_Facilities(Physiology)/Physical_Exercise_-_Regional_Blood_Flow.aspx

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 http://www.tomhsiung.com/wordpress/2014/03/the-regular-of-extracellular-fluids-adh-secretion-and-renin-angiotensin-system/ .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

Factors That Affect GFR

April 16, 2014 Physiology and Pathophysiology 1 comment , , ,

Glomerular filtration rate (GFR) is the amount of plasma ultrafiltrate formed each minute in both kidneys. For substances that are nontoxic and not metabolized by the body can be used to measure GFR. Renal plasma clearance of this substance can be the GFR. The renal plasma clearance is the volume of plasma from which a substance is completely removed by the kidney in a given amount of time. The amount of that substance that appears in the urine per unit of time is the result of the renal filtering of a certain number of milliliters of plasma that contained this amount.

The GFR in a healthy adult of average size is approximately 125 mL/min.

The factors governing filtration across the glomerular capillaries are the size of the capillary bed, the permeability of the capillaries, and the hydrostatic and osmotic pressure gradients across the capillary wall. That is,

GFR = k[(PGC –  PT) – (πGC – πT)]

PGC is the mean hydrostatic pressure in the glomerular capillaries, PT is the mean hydrostatic pressure in the tubule, πGC is the oncotic pressure of the plasma in the glomerular capillaries, and πT is the oncotic pressure of the filtrate in the tubule. Normally, the πT is negligible and can be ignored. So the GFR can be calced as follows:

GFR = k[(PGC –  PT) – πGC]

Factors that affect parameters in the formula above can affect GFR.

Renal plasma flow would alter GFR positively. Since the increase of renal plasma flow increase the amount of volume of plasma filtrated by glomerular in every unit of time. Besides, as the renal plasma flow increases, the rate of increase in πGC is slow down (flow-limited exchange) and the distance along the glomerular capillaries is prolonged, which makes filtrate increased and the GFR.Screen Shot 2015-02-11 at 6.19.00 PM

Factors that alter renal plasma flow such as constriction of renal blood arterial vessels, afferent arteriolar, low effective circulatory volume etc affect GFR as described above, and stimulation of the renal nerves (sympathetic efferent fibers) also cause the vasoconstriction of renal blood arterial vessels. Note that 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 relative constant (auto-regualtion).

PS: the stimulation of renal sympathetic fibers increases secretion of renin, increases reabsorption of sodium by tubule directly, and decreases GFR.

Changes in glomerular capillary hydrostatic pressure would affect GFR directly as explained in the formula above. The constriction of efferent arteriolar would increase the glomerular capillary hydrostatic pressure and to maintain the GFR to some degree (When renal blood flow decreases, the constriction of efferent arteriolar due to effect of AngII help to maintain the GFR). Changes in Kf and hydrostatic pressure in Bowman's capsule would affect GFR.

Changes in glomerular capillary permeability and effective filtration surface area would affect GFR.

PS: At low perfusion pressures, angII also appears to play a role by constricting the efferent arterioles, thus maintaining the GFR. This is believed to be the explanation of the renal failure that sometimes develops in patients with poor renal perfusion who are treated with drugs that inhibit angiotensin-converting enzyme (that is, ACEIs).


Screen Shot 2016-07-10 at 7.32.03 PMWrite Again – GFR and Its Determinants

The glomerular filtrate contains most inorganic ions and low-molecular-weight organic solutes in virtually the same concentrations as in the plasma. It also contains small plasma peptides and a very limited amount of albumin. Filtered fluid must pass through a 3-layered glomerular filtration barrier. The first layer, the endothelial cells of the capillaries, is perforated by many large fenestrae ("windows"), like a slice of Swiss cheese, which occupy about 10% of the endothelial surface area. They are freely permeable to everything in the blood except cells and platelets. The middle layer, the capillary basement membrane, is a gel-like acellular meshwork of glycoproteins and proteoglycans, with a structure like a kitchen sponge. The third layer consists of epithelial cells (podocytes) that surround the capillaries and rest on the capillary basement membrane. The podocytes have an unusual octopus-like structure. Small "fingers," called pedicels (or foot processes), extend from each arm of the podocyte and are embedded in the basement membrane. Pedicels from a given podocyte inter-digitate with the pedicels from adjacent podocytes. The pedicels are coated by a thick layer of extracellular material, which partially occludes the slits. Extremely thin processes called slit diaphragms bridge the slits between the pedicels. Slit diaphragms are widened versions of the tight junctions and adhering junctions that link all contiguous epithelial cells together and are like miniature ladders. The pedicels form the sides of the ladder, and the slit diaphragms are the rungs. Spaces between slit diaphragms constitute the path through which the filtrate, once it has passed through the endothelial cells and basement membrane, travels to enter Bowman's space.

Both the slit diaphragms and basement membrane are composed of an array of proteins, and while the basement membrane may contribute to the selectivity of the filtration barrier, integrity of the slit diaphragms is essential to prevent excessive leak of plasma protein. Some protein-wasting diseases are associated with abnormal slit diaphragm structure. The selectivity of the filtration barrier is crucial for renal function. The barrier has to be leaky enough to permite free passage of everything that should be filtered, such as organic waste, yet restrictive to plasma proteins that should not be filtered. Selectivity of the barrier is based on both molecular size and electrical charge. The filtration barrier of the renal corpuscle provides no hindrance to the movement of molecules with molecular weights less than 7000 Da, including all small ions, glucose, urea, amino acids, and many hormones. The filtration barrier almost totally excludes plasma albumin. The hindrance to plasma albumin is not 100%, howevver, and the glomerular filtrate does contain extremely small quantities of albumin, on the order of 10 mg/L or less. This is only about 0.02% of the concentration of albumin in plasma. Some small substances are partly or mostly bound to large plasma proteins and are thus not free to be filtered, even though the unbound fractions can easily move through the filtration barrier. This includes hydrophobic hormones of the steroid and thyroid categories and about 40% of the calcium in the blood.

For molecules with a molecular weight ranging from 7000 to 70,000 Da, the amount filtered becomes progressively smaller as teh molecule becomes larger. Thus, many normally occurring small- and medium-sized plasma peptides and proteins are actually filtered to a significant degree. Moreover, when certain small proteins appear in the plasma because of disease, considerable filtration of these may occur as well.

Electrical charge is the second variable determining filterability of macromolecules. For any given size, negatively charged macromolecules are filtered to a lesser extent, and positively charged macromolecules to a greater extent, than neutral molecules. This is because the surfaces of all the components of the filtration barrier (the cell coats of the endothelium, the basement membrane, and the cell coats of the slit diaphragms) contain fixed polyanions, which repel negatively charged macromolecules during filtration. Because almost all plasma proteins bear net negative charge, this electrical repulsion plays a very important restrictive role, enhancing that of purely size hindrance. In other words, if either albumin or the filtration barrier were not charged, even albumin would be filtered to a considerable degree. It must be emphasized that the negative charges in teh filtration membranes act as a hindrance only to macromolecules, not to mineral anions or low-molecular-weight organic anions. Thus, chloride and bicarbonate ions, despite their negative charge, are freely filtered.

Direct Determinants of Glomerular Filtration Rate

The rate of filtration in any capillary bed, including the glomeruli, is determined by the hydraulic permeability of the capillaries, their surface are, and the net filtration pressure acting (NFP) across them.

Rate of filtration = hydraulic permeability X surface area X NFP

Because it is difficult to estimate the surface area of a capillary bed, a parameter called the filtration coefficient (Kf) is used to denote the product of the hydraulic permeability and surface area. The NFP is the algebraic sum of the hydrostatic pressures and the osmotic pressures resulting from protein – the oncotic, or colloid osmotic pressures, – on the 2 sides of the capillary wall. There are 4 pressures to consider: 2 hydrostatic pressures and 2 oncotic pressures. These are known as Starling forces. In the glomerular capillaries

NFP = (PGC – PBC) – (πGC – πBC)

where PGC is glomerular capillary hydrostatic pressure, πBC is the oncotic pressure of fluid in Bowman's capsule, PBC is the hydrostatic pressure in Bowman's capsule, and πGC is the oncotic pressure in glomerular capillary plasma. Because there is normally little total protein in Bowman's capsulre, πBC may be taken as zero. Accordingly, the overall equation for GFR becomes

GFR = Kf X (PGC – PBC – πGC)

Figure 2-5 shows that the hydrostatic pressure is nearly constant within the glomeruli. This is because there are so many capillaries in parallel, and collectively they provide only a small resistance to flow, but the oncotic pressure in the glomerular capillaries does change substantially along the length of the glomeruli. As water is filtered out of the vascular space it leaves most of the protein behind, thereby increasing protein concentration and, hence, the oncotic pressure of the unfiltered plasma remaining in the glomerular capillaries. Mainly because of this large increase in oncotic pressure, the NFP decreases from the beginning of the glomerular capillaries to the end.

Screen Shot 2016-07-11 at 3.38.42 PMThe NFP when averaged over the whole length of the glomerulus is about 16 mm Hg. This average NFP is higher than that found in most nonrenal capillary beds. Taken together with a very high value for Kf, it accounts for the enormous filtration of 180 L of fluid/day (compared wtih 3L/day or so in all other capillary beds combined).

The GFR is not constant but shows fluctuations in differing physiological states and in disease. Its value must be tightly controlled. To understand control of the GFR, it is essential to see how a change in any one factor affects GFR under the assumption that all other factors are held constant. It provides a checklist to review when trying to understand how diseases or vasoactive chemical messengers and drugs change GFR. It should be noted that the major cause of decreased GFR in renal disease is not a change in these parameters within individual nephrons, but rather a decrease in the number of functioning nephrons. This reduces Kf.

Filtration coefficient (Kf)

  • Glomerular diseases
  • Contraction of glomerular mesangial cells

Changes in Kf are caused most often by glomerular disease, but also by normal physiological control. The detials are still not completely clear, but chemical messengers released within the kidneys cause contraction of glomerular mesangial cells. Such contraction may restrict flow through some of the capillary loops, effectively reducing the area available for filtration, Kf, and hence GFR.

Glomerular Capillary Hydrostatic Pressure (PGC)

  • Renal artery pressure
  • Renal blood flow
  • Changes in the resistance of the AAs and EAs

Hydrostatic pressure in the glomerular capillaries is influenced by many factors. We can depict the situation using the analogy of a leaking garden hose. If pressure in the pipes feeding the hose changes, the pressure in the hose and, hence, the rate of leak will be altered. Resistances in the hose also affect the leak. If we hink the hose upstream from the leak, pressure at the reigon of leak decreases and less water leaks out. However, if we hink the hose beyond the leak, this increase pressure at the region of leak and increases the leak rate. These same principles apply to PGC and GFR. First, change in renal arterial pressure causes a change in PGC in the same direction. If resistance remain constant, PGC rises and falls as renal artery pressure (and renal blood flow) rises and falls. This is a crucial point because arterial blood pressure shows considerable variability. Second, changes in the resistance of the afferent and EAs have opposite effects on PGC. An increase in afferent arteriolar resistance, which is upstream from the glomerulus, is like kinking the hose above the leak – it decrease PGC. An increase in efferent arteriolar resistance is down-stream from the glomerulus and is like kinking the hose beyond the leak – it increases PGC. Of course dialation of the AA raises PGC, and hence GFR, whereas dialation of the EA lowers PGC and GFR. It should also clear that when the afferent and efferent arteriolar resistances both change in the same direction, they exert opposing effects on PGC.

What is the significance of this? It means the kidney can regulate PGC and, hence, GFR independently of RBF.

Hydrostatic Pressure in Bowman's Capsule (PBC)

  • Urinary obstruction

Changes in pressure within Bowman's space are usually of very minor importance. However, obstruction anywhere along the tubule or in the external portions of the urinary system (e.g., the ureter) increases the tubular pressure everywhere proximal to the occlusion, all the way back to Bowman's capsulre. The result is to decrease GFR.

Oncotic Pressure in Glomerular Capillary PlasmaGC)

  • Arterial plasma protein concentration
  • Renal plasma flow

Oncotic pressure in the plasma at the very beginning of the glomerular capillaries is the oncotic pressure of systemic arterial plasma. Accordingly, a decrease in arterial plasma protein concentration, as occurs, for example, in liver disease, decreases arterial oncotic pressure and tends to increase GFR, whereas increased arterial oncotic pressure tends to reduce GFR.

However, recall that πGC is the same as arterial oncotic pressure only at the very begining of the glomerular capillaries; πGC then increases somewhat along the glomerular capillaries as protein-free flid filters out of the capillary, concentrating the protein left behind. This means that NFP and, hence, filtration progressively decrease along the capillary length. Accordingly, anything that causes a steeper increase in πGC tends to lower average NFP and hence GFR.

Such a steep increase in oncotic pressure occurs in conditions of low RBF. When RBF is low, the filtration process removes a relatively larger fraction of the plasma, leaving a smaller vlume of plasma behind in the glomeruli still containing all the plasma protein. The πGC reaches a final value at the end of the glomerular capillaries that is higher than normal. This lowers average NFP and, hence, GFR. Conversely, a high RBF, all other factors remaining constant, causes πGC to increase less steeply and reach a final value at the end of the capillaries that is less than normal, which increases the GFR.

As blood is composed of cells and plasma, we can describe the flow of plasma per se, the renal plasma flow (RPF). Variations in the relative amounts of plasma that are filtered can be expressed as a filtration fraction: the ratio RPF/GFR, which is normally about 20%, that is, about 20% of the plasma entering the kidney is removed from the blood and put into the Bowman's space. The increase in πGC along the glomerular capillaries is directly proportional to the filtration fraction (i.e., if relatively more of the plasma is filtered, the increase in πGC is greater). If the filtration fraction has changed, it is certain that there has also been a proportional change in πGC and that this has played a role in altering GFR.

Filtered Load

A term we use in other chapters is filtered load. It is the amount of substance that is filtered per unit time. For freely filtered substances, the filtered load is the product of GFR and plasma concentration. Consider sodium. Its normal plasma concentration is 140 mEq/L, or 0.14 mEq/mL. A normal GFR in healthy young adult males is 125 mL/min, so the filtered load of sodium is 0.14 mEq/mL X 125 mL/min = 17.5 mEq/min. We can do the same calculation for any other substance, being careful in each case to be aware of the unit of measure in which concentration is expressed. The filtered load is what is presented to the rest of the nephron to handle. The filtered load varies with plasma concentration and GFR. An increase in GFR, at constant plasma concentration, increases the filtered load, as does an increase in plasma concentration at constant GFR. Variations in filtered load play a major role in the renal handling of many substances.