Regulation of Water Excretion

July 23, 2016 Cardiology, Critical Care, Nephrology, Physiology and Pathophysiology No comments , , , , ,

Water excretion, as with sodium excretion, is regulated in partnership with the CV system. Central goals in regulating both salt and water excretion are to: 1).preserve vascular volume and 2).maintain plasma osmolality at a level that is healthy for tissue cells. The main regulators of water excretion, not surprisingly, relate to osmolality and volume.

Quantitatively, renal water excretion is determined by 2 values: 1).the amount of solute in the urine and 2).the osmolality of the urine.

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Urine water excretion = urine solute excretion/urine osmolality

Excreted solute consists mostly of organic waste and excess electrolytes. In a given metabolic state, the rate of organic waste excretion is more or less constant, and is not altered for purposes of controlling water excretion. Electrolyte excretion is highly regulated, but more to achieve balance of individual substances like sodium and potassium than to control water excretion per se. Given that solute excretion is so variable, the main way the body controls water excretion in normal circumstances is to control urine osmolality. In other words, given a certain amount of solute that is excreted, the body controls the amount of water accompanying it by controlling urine osmolality.

When the body excretes urine that is more dilute than plasma (osmolality below 285 mOsm/kg H2O), the body is excreting "free water" (like adding pure water to otherwise isosmotic urine). Conversely, when the excreted urine is more concentrated than plasma, there is "negative free water" excretion. It is as if the body has reclaimed pure water from otherwise isosmotic urine.

The kidneys first generate hypo-osmotic tubular fluid in the loop of Henle. Then, as the fluid subsequently flows through the collecting duct system, variable amounts of water are reabsorbed by allowing the tubular fluid to equilibrate to varying degrees with the surrounding interstitum. The final urine osmolality, and hence final volume, depends on the peak medullary osmolality and how closely the tubular osmolality approaches that value. We also know that equilibration with the interstitium is a function of water permeability in the collecting ducts under the control of the hormone antidiuretic hormone (ADH). Therefore the regulation of water excretion, that is independent of solute excretion, focuses on control over ADH secretion.

Osmoreceptor Control of ADH Secretion

Plasma osmolality is one of the most tightly regulated variables in the body. Plasma osmolality is set mainly by the ratio of ECF sodium (plus its assocaited anions) to water. Other solutes (e.g., glucose and potassium) make some contribution, but those other solutes are regulated for reasons other than plasma osmolality. Thus, except under unusual circumstances such as severe hyperglycemia, variations in plasma osmolality mostly reflect variations in sodium concentration. If the body keeps the inputs and outputs of sodium and water matched in lock step, osmolality remains constant. But inputs are often not matched. The major effect of gaining or losing water or salt without corresponding changes in the other is a change in the osmolality of the body fluids. When osmolality deviates from normal, strong reflexes come into play to change ADH secretion, and thus change the excretion of water.

Baroreceptor Control of ADH Secretion

There is another major influence on ADH secretion. This originates in systemic baroreceptors. A decreased extracellular volume or major decrease in arterial pressure reflexively activates increased ADH secretion. The response is mediated by neural pathways originating in cardiopulmonary baroreceptors, and if arterial pressure decreases, from arterial baroreceptors.

Decreased CV pressures cause less firing by the baroreceptors, which relieves inhibition of stimulatory pathways and results in more ADH secretion. In effect, the low CV pressures are interpreted as low volume, and the response of increased ADH appropriately serves to minimize loss of water. Conversely, baroreceptors are stimualted by increased CV pressures, interpreted as excess volume, and this causes inhibition of ADH secretion. The decrease in ADH results in decreased reabsorption of water in the collecting ducts, and more excretion. The adaptive value of these baroreceptor reflexes is to help stabilize ECF volume and, hence, blood pressure.

There is a second adaptive value to this reflex: Large decreases in plasma volume, as might occur after a major hemorrhage, elicit such high concentrations of ADH – much higher than those needed to produce maximal antidiuresis – that the hormone is able to exert direct vasoconstrictor effects on arteriolar smooth muscle. The result is increased total peripheral resistance, which helps restore arterial blood pressure independently of the slower restoration of body fluid volumes. Renal arterioles and mesangial cells also participate in this constrictor response, and so a high plasma concentration of ADH, quite apart form its effect on water permeability and sodium reabsorption in the distal nephron, promotes retention of both sodium and water by lowering GFR.


The cells that synthesize ADH in the hypothalamus also receive synaptic input from many other brain areas. Thus, ADH secretion and, hence, urine flow can be altered by pain, fear, and a variety of other factors, including drugs such as alcohol, which inhibits ADH release. However, this complexity should not obscure the generalization that ADH secretion is determined over the long term primarily by the states of body fluid osmolality and plasma volume.

We have described 2 different major afferent pathways controlling the ADH-secreting hypothalamic cells: 1 from baroreceptors and 1 from osmoreceptors. These hypothalamic cells are, therefore, true integrators, whose activity is determined by the total synaptic input to them. Thus, a simultaneous increase in plasma volume and decrease in body fluid osmolality causes strong inhibition of ADH secretion. Conversely, a simultaneous decrease in plasma volume and increase in osmolality produces very marked stimulation of ADH secretion. However, what happens when baroreceptor and osmoreceptor inputs oppose each other? In general, because of the high sensitivity of the osmoreceptors, the osmoreceptor influence predominates over that of the baroreceptors when changes in osmolality and plasma volume are small to moderate. However, a dangerous reduction in plasma volume will take precedence over decreased body fluid osmolality in influencing ADH secretion; under such conditions, water is retained in excess of solute even though the body fluids become hypo-osmotic (for the same reason, plasma sodium concentration decreases). In essence, when blood volume reaches a life-threatening low level, it is more important for the body to preserve vascular volume and thus ensure an adequate cardiac output than it is to preserve normal osmolality.

Thirst and Salt Appetite

Deficits of salt and water cannot be corrected by renal conservation, and ingestion is the ultimate compensatory mechanism. The subjective feeling of thirst, which drives one to obtain and ingest water, is stimulated both by reduced plasma volume and by increased body fluid osmolality. Note that these are precisely the same changes that stimulate ADH production, and the receptors – osmoreceptors and the nerve cells that respond to the CV baroreceptors – that initiate the ADH-controlling reflexes are near those that initiate thirst. The thirst response, however, is significantly less sensitive than the ADH response.

There are also other pathways controlling thirst. For example, dryness of the mouth and throat causes profound thirst, which is relieved by merely moistening them. Also, when animals such as the camel (and humans, to a lesser extent) become markedly dehydrated, they will rapidly drink just enough water to replace their previous losses and then stop. What is amazing is that when the stop, the water has not yet had time to be absorbed from the gastrointestinal tract into the blood.

Effect of Respiratory Activity on Circulation

June 21, 2016 Cardiology, Critical Care, Physiology and Pathophysiology No comments , , , , , , , , ,

The physical processes associated with inhaling air into and exhaling air out of the lungs can have major effects on venous return and cardiac output. During a normal inspiration, intrathoracic pressure falls from approximately negative 2 mm Hg to approximately negative 7 mm Hg as the diaphragm contracts and the chest wall expands. It rises again by an equal amount during expiration. These periodic pressure fluctuations not only promote air movement into and out of the lungs but also are transmitted through the thin walls of the great veins in the thorax to influence venous return to the heart from the periphery. Because of the unidirectional nature of venous valves, venous return is increased more by inspiration than it is decreased by expiration. The net effect is that venous return from the periphery is generally facilitated by the periodic fluctuations in central venous pressure caused by respiration. This phenomenon is often referred to as the "respiratory pump."

Cyclical alterations in intrathoracic pressure with normal breathing evoke primary disturbances in blood flow and distribution within the cardiovascular system. Some of these disturbances and compensatory responses are illustrated in Figure 10-1. Filling of the right side of the heart is transiently increased during inspiration (due to decreased CVP and increased venous return which increases the RVEDV) and stroke volume and thus cardiac output are transiently increased. In addition, the reduction in pulmonary vascular resistance that accompanies inspiration reduces the right ventricular afterload, which contributes to a transient increase in right ventricular stroke volume. Because changes in output of the right side of the heart induce changes in output of the left side of the heart within a few beats, the net effect of inspiration will be a transient increase in stroke volume and cardiac output from the left ventricle. This will lead to a transient increase in arterial pressure and a transient increase in firing of the arterial baroreceptors. The short-term cardiovascular reflex results via arterial baroreceptors are increased parasympathetic nerve activity, decreasing sympathetic nerve activity, and a decrease in heart rate.

The inspiration-induced decrease in intrathoracic pressure will also stretch low-pressure (volume) cardiopulmonary baroreceptors in the vascular and cardiac walls and will increase their firing rate (which results in a drop in BP set point). These low-pressure baroreceptor inputs will add to the information from the high-pressure baroreceptors and promote similar pressure-lowering ouputs from the medullary cardiovascular centers.

Lung mechanoreceptors located primarily within the airways are also stretched during normal inspiration. Unlike the first two mechanisms, their input into the medullary centers results in an inhibition of the normal tonic vagal activity to the sinoatrial node, causing a transient increase in the heart rate.

The Regulation of Circulation (Central Mechanisms)

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

Hu_Shih_1960_colorIn humans and other mammals, multiple cardiovascular regulatory mechanisms have evolved. These mechanisms increase or decrease the blood supply to active tissues and increase or decrease heat loss from the body by redistributing the blood.

In the face of challenges such as hemorrhage, they maintain the blood  flow to the heart and brain. When the challenge faced is severe, flow to these vital organs is maintained at the expense of the circulation to the rest of the body.

Generally, body redistributes the circulation through systemic and local mechanisms. With the sympathetic nerve system’s systemic effects via signals from CNS, the diameter of vascular system (arteriolar vasoconstriction) decreases and the stroke volume (SV) and heart rate (HR), which in together contribute a rise/maintain in blood pressure.

For vein system, venoconstriction and a decrease in the stores of blood in the venous reservoirs usually accompany increases in arteriolar constriction, although changes in the capacitance vessels do not always parallel changes in the resistance vessels.

Central Mechanisms

The systemic regulation for vascular system (we doesn’t discuss the affects on heart in this thread) consists of the centre nerve system (1), the baroreceptors (2), cardiopulmonary receptors (3), carotid and aortic chemoreceptors (4), central chemoreceptors (5), the afferent nerve system (glossopharyngeal nerve, vagus nerve) (6), the autonomic nerve system (7), and the endocrine system (primary the adrenal medulla). The CNS play its role as the vascular control centre – the vasomotor. Information or “sense” perceived by baroreceptors, cardiopulmonary receptors, and chemoreceptors is transferred into vascular center via the afferent nerve system. Thereafter, vascular center analyses the inputs and form regulatory signals which then are transferred to the effector tissues or organs via the autonomic nerve system. However, several fibres from other parts of the nervous system can alter the activity of RVLM.


Afferent Innervation

The baroreceptors are stretch receptors in the walls of the heart and blood vessels. However, in this thread the term “baroreceptor” is used to describe the baroreceptors in the arterial circulation, in order to distinguish them from cardiopulmonary receptors which are located in the low-pressure part of the circulation. The carotid sinus and aortic arch receptors monitor the arterial circulation, whereas cardiopulmonary receptors are located in the walls of the right and left atria at the entrance of the superior and inferior venue cave and the pulmonary veins, as well as in the pulmonary circulation. Inputs (intensity of stretch, more intensive, more frequent the rate of discharge of the receptors) are transferred through the afferent fibers to the CNS. These afferent fibers belong to glossopharyngeal nerve (carotid sinus nerve) and the vagus nerve (aortic depressor nerve).

The cardiopulmonary receptors are stretch receptors located in the walls of the right and left atria at the entrance of the superior and inferior venue cave and the pulmonary circulation, where the pressure of the circulation is low. Among cardiopulmonary receptors, the atria receptors are of two types, which also response to stretch: 1.those that discharge primarily during atrial systole (type A), and those that discharge primarily late in diastole, at the time of peak atrial filling (type B). The discharge of type B cardiopulmonary receptors is increased when venous return is increased and decreased by positive-pressure breathing, including that these receptors respond primarily to distention of the atrial walls.

The peripheral chemoreceptors locate in the carotid and aortic bodies where the rates of blood flow is very high. These receptors are activated by reduction of PaO2/pH and/or increase of PaCO2/[H+]. More accurately, the rates of discharge of peripheral chemoreceptors get more intensively with low PaO2/pH and/or high PaCO2/[H+], which then are transferred into the CNS and increase the excitement of vasomotor. Therefore the final result is vasoconstriction. Note that when blood flow is compromised due to settings such as hemorrhage etc., the PaO2/pH and PaCO2/[H+] in peripheral chemoreceptors is significant affected due to the lack of blood supply.

Chemoreceptor discharge may also contribute to the production of Mayer waves. These should not be confused with Traube-Hering waves, which are flections in blood pressure synchronised with respiration. The Mayer waves are slow, regular oscillations in arterial pressure that occur at the rate of about one per 20-40 second during hypotension. Under these conditions, hypoxia stimulates the chemoreceptors. The stimulation raises the blood pressure, which improves the blood flow in the receptor organs and eliminates the stimulus to the chemoreceptors, so that the pressure falls and a new cycle is initiated.

The central chemoreceptors. Central chemoreceptors locate on the ventrolateral surface of the medulla. These receptors are activated by reduction of PaO2/pH and/or increase of PaCO2/[H+]. In cases such as when intracranial pressure is increased, the blood supply to RVLM neurons is compromised, and the local hypoxia and hypercapnia increase their discharge. However, a change in plasma pH alone will not stimulate central chemoreceptors as H+ are not able to diffuse across the blood–brain barrier into the CSF. Only CO2 levels affect this as it can diffuse across, reacting with H2O to form carbonic acid and thus decrease pH. Central chemoreception remains, in this way, distinct from peripheral chemoreceptors.Screen Shot 2015-02-01 at 7.52.22 PM

Efferent Innervation

Most of the vasculature is an example of an autonomic effector organ that receives innervation from the sympathetic but not the parasympathetic division of the autonomic nervous system. However, few walls of arterioles, for instance the arterioles in skeletal muscles, are innervated by cholinergic fibres [still sympathetic nerves], which dilate the vessels after stimuli. However, in humans, evidence for a sympathetic cholinergic vasodilator system is lacking. It seems that activation of β2-adrenoceptors on skeletal muscle blood vessels promotes vasodilation. It is more likely that vasodilation of skeletal muscle vasculature in response to activation of the sympathetic nervous system is due to the action of epinephrine released from the adrenal medulla. And more is that a few exceptions exists that the arteries in the erectile tissue of the reproductive organs, uterine and some facial blood vessels, and blood vessels in salivary glands, may also be controlled by parasympathetic nerves. For the detail of autonomic nerves system please refer to thread of “The Pain – The Basic Concepts” at

Sympathetic noradrenergic fibers terminate on vascular smooth muscle in all parts of the body to mediate vasoconstriction. For the arterial and capillary system (aorta, artery, small artery, arteriole, metarteriole, and capillary), the walls of the aorta and other arteries of large diameter contain a relatively large amount of elastic tissue, primarily located in the inner and external elastic laminas. The walls of the arterioles contain less elastic tissue but much more smooth muscle. The innervation of metarterioles is unsettled. The openings of capillaries are sounded on the upstream side by minute smooth muscle called pre capillary sphincters, which are not innervated.

Control Center

The cardiovascular system is under neural influences coming from several parts of the brain stem, forebrain, and insular cortex. One of the major sources of excitatory input to sympathetic nerves controlling the vasculature is a group of neurons located near the pill surface of the medulla in the rostral ventrolateral medulla (RVLM). This region is sometimes called a vasomotor area. The axons of RVLM neurons course dorsally and medially and then descend in the lateral column of the spinal cord to the thoracolumbar intermediolateral gray column (IML). They contain phenylethanolamine-N-methyltransferase (PNMT), but it appears that the excitatory transmitter they secrete is glutamate rather than epinephrine.

The activity of RVLM neurons (the more intensive the RVLM discharge, the more intensive the activity of autonomic nerve system [primary the sympathetic nerve system]) is determined by many factors. They include not only the very important fibres from material baroreceptors, cardiopulmonary receptors, and chemoreceptors, but also fibres from other parts of the nervous system. In addition, some stimuli act directly on the vasomotor area. They include,

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1.Descending tracts to the vasomotor area from the cerebral cortex (particularly the limbic cortex) that relay in the hypothalamus. These fibres are responsible for the blood pressure rise and tachycardia (the heart) produced by emotions such as stress, sexual excitement, and anger. The connections between the hypothalamus and the vasomotor area are reciprocal, with afferents from the brain stem closing the loop.

2.Inflation of the lungs, which causes inhibition of vasomotor discharge via afferent fibers of vagal nerve.

3.Pain usually causes a rise in blood pressure via afferent impulses in the reticular formation converging in the RVLM. However, prolonged severe pain may cause vasodilation and fainting.

4.The activity in afferents from exercising muscles probably exerts a similar pressor effect via a pathway to the RVLM. The pressor response to stimulation of somatic afferent nerves is called the somatosympathetic reflex.

Parasympathetic Motor Center

The medulla is also a major site of origin of excitatory input to cardiac vagal motor neurons in the nucleus ambiguus. The significance of parasympathetic motor neurons is that, release of acetylcholine from vagal nerve terminals inhibits the release of norepinephrine from sympathetic nerve terminals, which can enhance the effects of vagal nerve activation on the effector (the heart). This effect is induced by cholinergic receptors (adrenergic receptors for sympathetic system vice versa) that modulate transmitter release from nerve endings (see Clinical Pharmacology).