Actions of Vasopressin

VP is the key regulator of renal water excretion and the hormone has a central role in fluid balance. However, the physiology of VP encompasses a wider context within the integrated neuro- humoral response to changes in cardiovascular status and stress.

Vasopressin Receptors

VP action is mediated by binding to specific receptors on the cell membrane of target cells. There are three VP receptor (V- R) sub types, encoded by different genes (Table 1). All have seven transmembrane spanning domains, and all are G- protein coupled. They differ in tissue distribution, signal transduction mechanisms, and function. There is 70– 80% human– rat subtype homology at the amino acid level. The human V2- R gene has been mapped to Xq28. The murine V2- R gene maps to a syntenic X- chromosome locus.

Table1. Vasopressin receptor subtypes

Renal Effects of VP

 Although VP has multiple actions, its principle physiological effect is in the regulation of water reabsorption in the distal nephron. The hair- pin structure and electrolyte transport processes of the nephron allow the kidney to both concentrate and dilute urine in response to the prevailing circulating VP concentration. Active transport of solute out of the thick ascending loop of Henle generates an osmolar gradient in the renal interstitium which increases from renal cortex to inner medulla, a gradient through which distal parts of the nephron pass enroute to the collecting system. This is the basis of the renal countercurrent osmolar exchange mechanism. The presence of selective water channel proteins (aquaporins) in the wall of the distal nephron allows reabsorption of water from the duct lumen along an osmotic gradient, and excretion of concentrated urine

A wide range of aquaporins (AQPs) has been identified. They act as passive pores for small substrates and are divided into two families: the water only channels; and the aquaglyceroporins that can conduct other small molecules such as glycerol and urea. As with other membrane channels, specific structural arrangements within the primary, secondary, and tertiary structure convey the three functional characteristics of permeation, selectivity, and gating. AQPs have a common structure consisting of two tandem re peats (each formed from three transmembrane domains), together with two highly conserved loops containing the signature motif asparagine- proline- alanine (NPA). AQP channels are formed by a tertiary complex of homo- tetramers within the cell membrane, pro viding four functionally independent pores with an additional central pore. Water can pass through all the four independent channels of water- permeable AQPs. The central pore may act as independent channel in some AQPs.

Seven AQPs are found in the kidney: AQP1– 4 and AQP6– 8. AQP1 is constitutively expressed in the proximal tubule and descending loop of Henle, where it facilitates isotonic fluid movement. Loss of function mutations of AQP1 in man lead to defective renal water conservation. AQP3 and AQP4 are both expressed in the basolateral membrane of collecting duct cells in the distal nephron, where they facilitate the movement of water from the collecting duct cells into the renal interstitium. AQP2 is expressed on the luminal surface of collecting duct cells and is the water channel re sponsible for VP- dependant water transport from the lumen of the nephron into the collecting duct cells. The binding of VP to V2- Rs on the interstitial surface of collecting duct cells produces increases in expression of AQP2. The increase is biphasic: one requiring new AQP2 protein synthesis and one which is independent of new protein synthesis. V2- R activation triggers an intracellular phosphorylation cascade leading activation of the nuclear transcription factor CREB and expression of c- Fos and stimulation of AQP2 gene ex pression through CRE and AP- 1 response elements in the AQP2 gene promoter. V2- R activation also stimulates an immediate increase in AQP2 activity by accelerating trafficking and assembly of presynthesized AQP2 protein into functional, homo- tetrameric water channels in luminal cell membranes.

As VP levels rise, there is a sigmoid relationship between plasma VP concentration and urine osmolality, with maximum urine con centration achieved at plasma VP concentrations of 3– 4 pmol/ L (Figure 1). Following persistent VP secretion, antidiuresis may diminish. Downregulation of both V2- R function and AQP2 expression may be responsible for this escape phenomenon. Maximum diuresis occurs at plasma VP concentrations of 0.5 pmol/ L or less.

Fig1. The relationship of plasma vasopressin concentration to urine concentrating ability. There is a sigmoid relationship between plasma vasopressin concentration and urine osmolality, with maximum urine concentration occurring at plasma vasopressin concentrations of 4– 6 pmol/ L. There is a range of response in the normal population depicted by the grey area, within which an individual response is demonstrated.

VP has additional effects at other sites in the nephron, which serve to augment renal concentrating ability. VP decreases medullary blood flow, stimulates active urea transport in the distal collecting duct and stimulates active sodium transport into the renal interstitium. VP also stimulates a bi- phasic up- regulation of bumetanide- sensitive sodium- potassium- chloride cotransporter (SLC12A1) expression in the thick ascending loop of Henle. VP both accelerates post- translational processing/ trafficking of presynthesized SCLC12A1 and increases SCLC12A1 gene expression.

Cardiovascular Effects of VP

VP is a potent pressor agent, its effects mediated via a specific mem brane receptor (V1a- R). Systemic effects on arterial blood pressure are only apparent at high concentrations due to compensatory buffering haemodynamic mechanisms. Nevertheless, VP is important in maintaining blood pressure in mild volume depletion. The most striking vascular effects of VP are in the regulation of regional blood f low. The sensitivity of vascular smooth muscle to the pressor effects of VP vary according to the vascular bed; vasoconstriction of splanchnic, hepatic, and renal vessels occurring at VP concentrations close to the physiological range. Furthermore, there are differential pressor responses within a given vascular bed; selective effects on intrarenal vessels resulting in redistribution of renal blood f low from medulla to cortex. Such effects suggest that baroregulated VP release constitutes one of the key physiological mediators of the integrated haemodynamic response to volume depletion.

Effects of VP on the Pituitary

 VP is an ACTH secretagogue, acting through pituitary corticotroph- specific V3- Rs. Though the effect is weak in isolation, VP and C- reactive protein (CRF) act synergistically. VP and CRF colocalize in neurohypophyseal parvicellular neurones projecting to the median eminence and the neurohypophyseal portal blood supply of the anterior pituitary. Levels of both VP and CRF in these neurones are inversely related to glucocorticoid levels, clearly suggesting a role in feedback regulation.

Behavioural Effects of VP

Vasopressinergic fibres and V- Rs are present in many areas of the brain, including the cerebral cortex and limbic system. These extensive neural networks are anatomically and functionally independent of the neurohypophysis. In rodents, these central vasopressinergic systems have key roles in mediating complex social behaviour such as mating patterns. There are similar emerging data in man. Association studies link V1a- R gene sequence variation with a range of behaviours. Dysregulation of central VP action may be a distal end point in conditions characterized by complex altered social and emotional behaviour.

Miscellaneous Effects of VP

 Several additional actions of VP are listed in Table 2.

Table2. Miscellaneous effects of VP

Osmoregulation of in VP Release

In line with the hormone’s key role in body fluid homeostasis, plasma osmolality is the most important determinant of VP secretion. Working in tandem, the combined osmoregulatory system for thirst and VP secretion maintain plasma osmolality within the narrow limits of 284– 295 mOsml/ kg. The osmoregulation of VP re lease and the physiological relationship between plasma osmolality and plasma VP concentration is described by three characteristics; the linear relationship between plasma osmolality and plasma VP concentration; the osmotic threshold or ‘set point’ for VP release: and the sensitivity of the osmoregulatory mechanism.

Increases in plasma osmolality increase plasma VP concentra tions in a linear manner (Figure 2). The abscissal intercept of this regression line, 284 mOsml/ kg, indicates the mean ‘osmotic threshold’ for VP release: the mean plasma osmolality above which plasma VP starts to increase. Though there is no level of plasma osmolality below which VP release is completely suppressed, though such low levels of VP have little antidiuretic effect. The concept of a threshold of VP release thus remains a pragmatic means to characterize the physiology of osmoregulation; VP release being increased from a basal rate by activation of stimulatory osmoreceptor afferents, and decreased to minimal values by removal of this drive and the activation of synergistic inhibitory afferents. The slope of the regression line reflects the sensitivity of osmoregulated VP release. There are considerable interindividual variations in both threshold and sensitivity of VP release. Twin studies indicate a strong heritable component in this variation. However, over time, these parameters are remarkably reproducible within an individual.

Fig2. Relationship between plasma osmolality and plasma vasopressin (VP) concentration during progressive hypertonicity induced by infusion of 855 mmol/ L saline in a group of healthy adults. LD represents the limit of detection of the assay, 0.3 pmol/ L.

There are several physiological situations where the tight relationship between plasma osmolality and VP concentration is lost. The act of drinking results in rapid suppression of VP release, in dependent of changes in osmolality. In addition, the rate of change of plasma osmolality can influence the VP response; rapid increases in plasma osmolality result in exaggerated VP release. The osmotic threshold for VP release is lowered in normal pregnancy, and a similar though smaller change occurs in the luteal phase of the menstrual cycle. Plasma VP concentrations increase with age, together with enhanced VP responses to osmotic stimulation. In contrast, thirst appreciation is blunted and fluid intake reduced. These changes, together with age- related decreases in renal handling of water loads and generation of maximal urine concentration, form the basis for the predisposition of older people to both hyper- and hyponatraemia.

Baroregulation of VP Release

 As a principle determinant of fluid homeostasis, VP is a key player in maintaining haemodynamic integrity. In contrast to osmoregulated VP release, progressive reduction in blood pressure produces an ex ponential increase in plasma VP. Falls in arterial blood pressure of 5– 10% are necessary to increase circulating VP concentrations in man. Importantly, baroregulated VP release can occur at low levels of plasma osmolality levels that would normally act to suppress VP production. This apparent ‘hierarchy’ of regulation is important when considering the integrated physiological response to volume depletion. It is a key pathophysiological mechanism underpinning the hyponatraemia resulting from effective circulating volume depletion.

Humoral Regulation of VP Release

 Changes in circulating volume and blood pressure trigger an auto nomic and endocrine cascade resulting in a coordinated physio logical response. Baroregulated VP responses can be modified by other neurohumoral influences triggered as part of this coordinated response: atrial natriuretic peptide (ANP) inhibiting and norepinephrine augmenting baroregulated VP release. The renin– angiotensin system (activated in effective volume depletion) is also intricately involved in the regulation of VP production. Circulating angiotensin II stimulates VP secretion, acting centrally at forebrain centres influencing SON and PVN activation. In addition, angiotensin II stimulates VP release via a direct effect on VP magnocellular neurones, where type 2 angiotensin II receptors have been identified. In the rat, ANP inhibits both osmo- and baro- stimulated VP release centrally.

Other Regulatory Mechanisms of VP Release

 Nausea and emesis are potent stimuli to VP release, independent of osmotic and haemodynamic status. Manipulation of abdominal contents is another powerful stimulus to VP release. Both contribute to the high plasma VP values and consequent impairment of water load excretion, observed after gastrointestinal surgery. VP release in response to these stimuli and others, such as neuroglycopaenia, justify its classification as a stress response hormone.

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Hypothalamic Control of Growth Hormone Secretion

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