Stimulated Arginine Vasopressin Release Research Articles

Vasopressin: a possible link between hypoxia and hypertension

Cardiovascular and respiratory diseases are frequently associated with transient and prolonged hypoxia, whereas hypoxia exerts pro-hypertensive effects, through stimulation of the sympathetic system and release of pressor endocrine factors. This review is focused on the role of arginine vasopressin (AVP) in dysregulation of the cardiovascular system during hypoxia associated with cardiovascular disorders. AVP is synthesized mainly in the neuroendocrine neurons of the hypothalamic paraventricular nucleus (PVN) and supraoptic nucleus (SON), which send axons to the posterior pituitary and various regions of the central nervous system (CNS). Vasopressinergic neurons are innervated by multiple neuronal projections releasing several neurotransmitters and other regulatory molecules. AVP interacts with V1a, V1b and V2 receptors that are present in the brain and peripheral organs, including the heart, vessels, lungs, and kidneys. Release of vasopressin is intensified during hypernatremia, hypovolemia, inflammation, stress, pain, and hypoxia which frequently occur in cardiovascular patients, and blood AVP concentration is markedly elevated in cardiovascular diseases associated with hypoxemia. There is evidence that hypoxia stimulates AVP release through stimulation of chemoreceptors. It is suggested that acting in the carotid bodies, AVP may fine-tune respiratory and hemodynamic responses to hypoxia and that this effect is intensified in hypertension. There is also evidence that during hypoxia, augmentation of pro-hypertensive effects of vasopressin may result from inappropriate interaction of this hormone with other compounds regulating the cardiovascular system (catecholamines, angiotensins, natriuretic peptides, steroids, nitric oxide). In conclusion, current literature indicates that abnormal mutual interactions between hypoxia and vasopressin may significantly contribute to pathogenesis of hypertension.

Tolvaptan therapy for massive edema in a patient with nephrotic syndrome

Nephrotic syndrome (NS) is characterized by water and sodium retention, which leads to edema. The non-osmotic stimulation of arginine vasopressin release from the pituitary gland has been implicated as one of the important factors in abnormal water retention in patients with NS. We present the initial description of a patient with massive edema caused by refractory nephrotic syndrome, which was effectively treated with tolvaptan, a selective oral vasopressin V2 receptor antagonist. Tolvaptan is effective for the treatment of massive edema caused by NS. Larger studies are needed in the future to fully assess the value and safety of tolvaptan use for this condition.

Hyponatraemia: more than just a marker of disease severity?

Hyponatraemia--the most common serum electrolyte disorder--has also emerged as an important marker of the severity and prognosis of important diseases such as heart failure and cirrhosis. Acute hyponatraemia can cause severe encephalopathy, but the rapid correction of chronic hyponatraemia can also profoundly impair brain function and even cause death. With the expanding elderly population and the increased prevalence of hyponatraemia in this segment of society, prospective studies are needed to examine whether correcting hyponatraemia in the elderly will diminish cognitive impairment, improve balance and reduce the incidence of falls and fractures. Given that polypharmacy is also common in the elderly population, the various medications that may stimulate arginine vasopressin release and/or enhance the hormone's action to increase water absorption must also be taken into consideration. Whether hyponatraemia in a patient with cancer is merely a marker of poor prognosis or whether its presence may alter the patient's quality of life remains to be examined. In any case, hyponatraemia can no longer be considered as just a biochemical bystander in the ill patient. A systematic diagnostic approach is necessary to determine the specific aetiology of a patient's hyponatraemia. Therapy must then be dictated not only by recognized reversible causes such as advanced hypothyroidism, adrenal insufficiency, diuretics or other medicines, but also by whether the hyponatraemia occurred acutely or chronically. Information is emerging that the vast majority of cases of hyponatraemia are caused by the nonosmotic release of arginine vasopressin. Now that vasopressin V2-receptor blockers are available, a new era of clinical investigation is necessary to examine whether hyponatraemia is just a marker of severe disease or whether correction of hyponatraemia could improve a patient's quality of life. Such an approach must involve prospective randomized studies in different groups of patients with hyponatraemia, including those with advanced heart failure, those with cirrhosis, patients with cancer, and the elderly.

Early stimulation of vasopressin release maintains circulating blood volume in alcohol intoxicated rodents

Acute alcohol intoxication (AAI) decreases mean arterial blood pressure (MABP), results in greater hypotension during hemorrhagic shock (HS), and impairs MABP recovery during fluid resuscitation from HS. The underlying mechanisms have been identified to include attenuation of neuroendocrine activation without alteration of pressor response. Whether AAI decreases blood volume, lowering tolerance to blood loss was not known. Chronically‐catheterized, adult male Sprague‐Dawley rats (250–300g) received a primed‐constant (2.5g/kg + 0.3g/kg/h) 15h intragastric infusion of alcohol or isocaloric/isovolumic dextrose (DEX). AAI resulted in an early and transient significant increase in urine output, decreased urine osmolality, and increased plasma osmolality. This was associated with a significant increase (43%; p<0.05) in circulating arginine vasopressin (AVP) 1h into the infusion. Blood volume and hematocrit were not different between the AAI and DEX groups at completion of the 15h infusion. These results suggest that AAI stimulates diuresis leading to increased plasma osmolality, which in turn stimulates AVP release decreasing urine output and restoring plasma osmolality. We conclude that decreased blood volume does not contribute to the impaired hemodynamic stability observed in AAI+HS. Supported by DOD PR‐054196 and NIAAA‐AA7577.

Different mechanisms mediate the in vivo aldosterone and corticosterone responses to 5-bromo-2'-deoxyuridine in rats.

The subcutaneous injection of 5'-bromo-2' deoxyuridine (BrdU) was found to raise the plasma concentrations of ACTH, aldosterone and corticosterone in rats. The aldosterone response was observed at a lower dose of BrdU and lasted for a longer period than those of ACTH and corticosterone (1.25 versus 2.50 mg/100 g body weight; 48 versus 24 h). Corticosterone response to BrdU was partially reversed by the ACTH-receptor antagonist corticotropin-inhibiting peptide (CIP), and aldosterone response by the arginine vasopressin (AVP) V1-receptor antagonist [amino-Pen1, Val4,D-Arg8]-vasopressin (AVP-A). The angiotensin-II (ANG-II)-receptor antagonist [Sar1, Val5, Ala8]-ANG-II (SAR) was ineffective. CIP, AVP-A and SAR, when administered alone, did not alter basal levels of ACTH, aldosterone and corticosterone. In light of these findings the following conclusions can be drawn: (i) BrdU stimulates the hypothalamo-pituitary-adrenal axis in rats, and this effect may influence the results of cell-kinetics studies carried out with the BrdU-labelling technique, especially in those tissue that are highly responsive to glucocorticoids (e.g. pituitary, adrenal and lymphatic tissues); and (ii) different mechanisms underlie the aldosterone and corticosterone secretagogue effects of BrdU, the former being at least in part dependent on the stimulation of AVP release and the latter on the rise in ACTH secretion.

Interactions between angiotensin II and arginine vasopressin in water homeostasis

Mice deficient in the angiotensin II type 1a (AT(1a)) receptor demonstrate a vasopressin-resistant nephrogenic diabetes insipidus. These knockout mice exhibit a threefold increase in 24-h urine excretion. Neither 2 weeks of exogenous vasopressin nor 5 days of fluid restriction reversed this polyuric state. This nephrogenic diabetes insipidus was associated with reductions in adenylyl cyclase protein and in the phosphorylated mitogen-activated protein kinase extracellular signal-regulated kinase 1/2. The results support an important interaction between vasopressin and angiotensin II in maximal urinary concentration.

Vasopressin and Aquaporin 2 in Clinical Disorders of Water Homeostasis

Impaired urinary dilution leading to water retention and hyponatremia may occur in patients with cardiac failure, cirrhosis, pregnancy, oxytocin administration, hypothyroidism, glucocorticoid, and mineralocorticoid deficiency. The mechanisms for these defects predominantly involve the nonosmotic stimulation of arginine vasopressin release with up-regulation of aquaporin 2 water channel expression and trafficking to the apical membrane of the principal cells of the collecting duct. These perturbations are reversed by V2 vasopressin receptor antagonists. In contrast, urinary concentration defects leading to polyuria are vasopressin resistant. They may involve several factors, such as impaired countercurrent concentration secondary to down-regulation of Na-K-2Cl cotransporter. Vasopressin-resistant down-regulation of aquaporin 2 expression has also been described as a factor in impaired urinary concentration.

Salusin β is a surrogate ligand of the mas-like G protein-coupled receptor MrgA1

The mas-like G protein-coupled receptors form a subfamily of G protein-coupled receptors that includes variable member numbers across different species and that have been shown to bind a wide variety of ligands from peptides to amino acid derivatives. While screening a library of peptides against different orphan G protein-coupled receptors, we found that human salusin β activates the mouse mas-like G protein-coupled receptor, mMrgA1 with an EC 50 of about 300 nM. Salusin β is a bioactive peptide recently discovered through bioinformatics analysis which stimulates arginine–vasopressin release from rat pituitary and causes rapid and profound hypotension and bradycardia. However, when we further analyzed the generality of the mMrgA1 activation, we found that human salusin β does not activate corresponding human mas-like G protein-coupled receptors. Our results show that human salusin β is a surrogate ligand of the mouse MrgA1 and raises a cautionary flag for experiments that analyze the pharmacological profiles of mas-like G protein-coupled receptors from different species.

Oxidative Stress and a Murine Superoxide Dismutase-1 Mutation Promoting Amyotrophic Lateral Sclerosis Alter Neurosecretion in the Hypothalamo-Neurohypophyseal Axis

In this study, we examined the effects of oxidative stress on a nitric oxide (NO)-regulated neuroendocrine function, the release of arginine vasopressin (AVP) by the hypothalamo-neurohypophyseal axis. Treatment of mouse-isolated hypothalami and neurointermediate lobes () with H₂O₂ increased AVP release. This effect was inhibited by copper-zinc superoxide dismutase-1 (SOD1) analogs. By measuring cGMP accumulation as an indicator of biologically active NO, we found that H₂O₂ treatment decreased cGMP formation in both hypothalami and . We have previously shown that NO inhibits AVP release by a cGMP-independent mechanism. Given that H₂O₂ stimulated AVP release, while it reduced cGMP production, our findings strongly suggest that oxidative damage affects neurosecretion by reducing NO availability. To test whether such a mechanism may operate under pathological conditions with pronounced oxidative stress, we compared neurosecretion in wild-type and transgenic mice carrying a mutated form of SOD1 associated with human familial amyotrophic lateral sclerosis. Reminiscent of the data obtained from H₂O₂-treated tissues, hypothalami and from SOD1 mutants displayed decreased cGMP accumulation and increased AVP release, compared with tissues from wild-type littermates. Since neuronal NO synthase expression was not modified, we conclude that the perturbed free radical metabolism associated with the SOD1 mutation is likely to trap NO, and thereby alter neurosecretion, a mechanism that can be exacerbated in specific physiopathological conditions.

Intragastric hypertonic saline increases vasopressin and central Fos immunoreactivity in conscious rats.

Although experimental evidence supports peripheral osmoreceptor modulation of arginine vasopressin (AVP) release, a local osmotic signal required for osmoreceptor activation has yet to be identified using physiological sodium loads. Additionally, the central pathway involved in peripheral control of AVP has not been clearly established. Experiments were conducted to examine the effect of intragastric saline on portal venous osmolarity, plasma AVP (P(AVP)), and Fos immunoreactivity. In anesthetized rats, intragastric infusion (2.9 ml) of hypertonic (600 mosM) saline significantly increased portal venous osmolarity while systemic blood osmolarity remained constant. In conscious rats, intragastric hypertonic saline significantly elevated P(AVP) (3.6 +/- 1.3 to 5.8 +/- 1.9 pg/ml), whereas no changes were observed in plasma osmolarity in either the isotonic (296.2 +/- 1.4 to 297.6 +/- 1.1 mosM) or hypertonic (291.7 +/- 1.7 to 291.4 +/- 1.8 mosM) group. Finally, intragastric hypertonic saline significantly increased Fos immunoreactivity in the nucleus of the solitary tract (NTS), area postrema (AP), lateral parabrachial nucleus (LPBN), supraoptic nucleus (SON), and paraventricular nucleus (PVN). These results indicate that intragastric hypertonic saline produces a portal venous osmotic signal that triggers peripheral osmoreceptors to stimulate AVP release while activating the NTS, AP, and LPBN in addition to the SON and PVN.

The NO synthase inhibitor l‐NNA depresses neurohypophysial vasopressin but not its precursor amidating enzymes in salt‐loaded rats

The arginine vasopressin (AVP) producing hypothalamo-neurohypophysial system also has high activities of NO-synthase. Vasopressin production and secretion is drastically upregulated during salt intake and the NO-producing enzyme may be involved. We have studied the influence of the NO-synthase inhibitor NG-nitro-L-arginine (L-NNA) on neurohypophysial and hypothalamic AVP and its amidating enzymes in salt-loaded and control rats as well as on stimulated AVP release in vitro in such rats. Rats were given 2% NaCl solution as the only fluid for 4 days and then returned to tap water. The specific amount of AVP (microgram (mg protein)-1) and the activities of peptidylglycine alpha-hydroxylating monooxygenase (PHM) and peptidyl-alpha-hydroxyglycine alpha-amidating lyase (PAL), components of its amidating processing enzyme in the supraoptic (SON) and paraventricular nuclear (PVN) regions, did not change during the salt-loading or the following recovery period. In contrast, the AVP and PHM and PAL in the neurohypophysis fell drastically during the salt loading. After that, PHM and PAL increased even more rapidly than AVP, the latter reaching control levels in about 10 days. Salt loading did not change the protein content of the neurohypophysis. When salt loading was performed after administration of L-NNA, the neurohypophysial AVP at the end of the salt loading and 3 days later was lower than in rats not receiving L-NNA, whereas PHM and PAL were not affected. Fractional AVP release from isolated neurohypophyses of salt loaded rats treated with L-NNA and stimulated with K+ was similar to that found in non-treated rats. It is suggested that L-NNA may affect translation or precursor processing of AVP.

IL-2 induces vasopressin release from the hypothalamus and the amygdala: role of nitric oxide-mediated signaling

The neuropeptide arginine vasopressin (AVP) can replace the cytokine interleukin 2 (IL-2) as a T-cell mitogen for the induction of interferon gamma (IFN gamma) expression in splenic cultures. IL-2-like and IL-2 receptor immunoreactivity have been reported in different brain regions, under normal and pathophysiological conditions. Regulatory functions for IL-2 in the CNS have been suggested. In addition to the spleen, AVP might also mediate some IL-2 effects centrally. In the present study, we evaluated the effect of IL-2 on the in vitro release of AVP from the hypothalamus and amygdala. In addition, we used these release systems to study the possible involvement of NO-mediated signaling in AVP release, based on the reported detection of nitric oxide synthase (NOS) in the hypothalamus and amygdala. IL-2 rapidly stimulates AVP release in both regions, in a calcium- and dose-dependent manner. In addition, nitroprusside also induces AVP release. Norepinephrine also induces AVP release from both the hypothalamus, as well as the amygdala. The norepinephrine-induced AVP release is antagonized by phentolamine, but not by propranolol, suggesting an alpha-adrenergic receptor-mediated AVP response in both brain regions. The IL-2- and acetylcholine-induced AVP release is antagonized by Ng-methyl-L-arginine, indicating a role for NO in this AVP release. Ng-methyl-L-arginine does not affect the norepinephrine-induced AVP release. A stimulatory effect of IL-2 on hypothalamic CRF release and plasma ACTH has already been reported. Our results suggest that in addition to CRF, AVP may also mediate the IL-2 stimulation of ACTH secretion. These data further suggest that in addition to the hypothalamus, the amygdala may also play a role in the bidirectional communication between neuroendocrine and immune systems. Understanding the mode of interaction between IL-2 with AVP could clarify the pathophysiologic or toxic effects of high brain levels of IL-2.

Dehydration-induced release of vasopressin involves activation of hypothalamic histaminergic neurons.

The hypothalamic neurotransmitter histamine (HA) induces arginine vasopressin (AVP) release when administered centrally. We studied and characterized this effect of HA with respect to receptor involvement. In addition, we studied the possible role of hypothalamic histaminergic neurons in the mediation of a physiological stimulus (dehydration) for AVP secretion. Intracerebroventricular administration of HA, the H1-receptor agonists 2(3-bromophenyl)HA and 2-thiazolylethylamine, or the H2-receptor agonists amthamine or 4-methyl-HA stimulated AVP secretion. The stimulatory action of HA on AVP was inhibited by pretreatment with the H1-receptor antagonist mepyramine or the H2-receptor antagonist cimetidine. Twenty-four hours of dehydration elevated the plasma osmolality from 298 +/- 3 to 310 +/- 3 mmol/liter and increased the plasma AVP concentration 4-fold. The hypothalamic content of HA and its metabolite tele-methyl-HA was elevated in response to dehydration, indicating an increased synthesis and release of hypothalamic HA. Dehydration-induced AVP secretion was lowered when neuronal HA synthesis was inhibited by the administration of (S) alpha-fluoromethylhistidine or when the animals were pretreated with the H3-receptor agonist R(alpha)methylhistamine, which inhibits the release and synthesis of HA, the H1-receptor antagonists mepyramine and cetirizine, or the H2-receptor antagonists cimetidine and ranitidine. We conclude that HA, via activation of both H1- and H2-receptors, stimulates AVP release and that HA is a physiological regulator of AVP secretion.

Dehydration-induced release of vasopressin involves activation of hypothalamic histaminergic neurons

The hypothalamic neurotransmitter histamine (HA) induces arginine vasopressin (AVP) release when administered centrally. We studied and characterized this effect of HA with respect to receptor involvement. In addition, we studied the possible role of hypothalamic histaminergic neurons in the mediation of a physiological stimulus (dehydration) for AVP secretion. Intracerebroventricular administration of HA, the H1-receptor agonists 2(3-bromophenyl)HA and 2-thiazolylethylamine, or the H2-receptor agonists amthamine or 4-methyl-HA stimulated AVP secretion. The stimulatory action of HA on AVP was inhibited by pretreatment with the H1-receptor antagonist mepyramine or the H2-receptor antagonist cimetidine. Twenty-four hours of dehydration elevated the plasma osmolality from 298 +/- 3 to 310 +/- 3 mmol/liter and increased the plasma AVP concentration 4-fold. The hypothalamic content of HA and its metabolite tele-methyl-HA was elevated in response to dehydration, indicating an increased synthesis and release of hypothalamic HA. Dehydration-induced AVP secretion was lowered when neuronal HA synthesis was inhibited by the administration of (S) alpha-fluoromethylhistidine or when the animals were pretreated with the H3-receptor agonist R(alpha)methylhistamine, which inhibits the release and synthesis of HA, the H1-receptor antagonists mepyramine and cetirizine, or the H2-receptor antagonists cimetidine and ranitidine. We conclude that HA, via activation of both H1- and H2-receptors, stimulates AVP release and that HA is a physiological regulator of AVP secretion.

Involvement of angiotensin receptor subtypes in osmotically induced release of vasopressin

We have previously shown that AT 1 and AT 2 angiotensin II (Ang II) receptors mediate the release of arginine vasopressin (AVP) to central injections of Ang II. In this study we have tested the hypothesis that Ang II, acting at AT 1 and AT 2 receptors in the brain, is involved in mediating osmotically stimulated AVP release. Adult Sprague-Dawley rats were fitted with intraventricular (i.v.t.) cannulas and catheters in the carotid artery and the femoral vein. Intraventricular injections of Ang II receptor antagonists specific to different subtypes of the receptor (AT 1 and AT 2) were given before a 30 min infusion of hypertonic (2.5 M) saline. Arterial blood samples were collected 5 min before and at two time points after (+ 15 min and + 30 min) beginning the saline infusion. We found that both losartan (AT 1 specific) and CGP42112A (AT 2 specific) significantly reduced osmotically induced release of AVP. PD123319 (AT 2 specific) had no effect of osmotically stimulated AVP release. A combined treatment of losartan +PD123319 was no more effective than losartan in blocking the AVP response. Since losartan was the most rapid and effective antagonist of osmotically stimulated AVP release, we conclude that AT 1 receptors are directly involved in the response. However, but since CGP42112A was also an effective antagonist and since, AT 2 receptors are located at sites distant from the hypothalamus, such as the locus ceruleus, they may also contribute to this response. We conclude that brain Ang II receptors are involved in osmotically stimulated AVP release.

Impairment of osmotically stimulated AVP release in patients with primary polydipsia

The secretion of arginine vasopressin (AVP) from the posterior pituitary is primarily and finely regulated by the osmolality of plasma. Even though a number of factors alter osmolality-induced release of AVP, there are no published data in humans that have addressed the role of chronic overhydration on this phenomenon. To address this problem we have identified eight patients with primary polydipsia using criteria not involving measurement of AVP, and have subjected them to standardized infusions of hypertonic saline. These patients had less AVP in both plasma and urine in relation to plasma osmolality than was found in normal subjects. In addition, their rate of rise of plasma and urine AVP was less than in normal subjects. Their osmotic threshold for AVP release may have been higher than normal. These data demonstrate that chronic overhydration in humans downregulates the release of AVP in response to hypertonicity. This phenomenon may explain the impairment of urine concentration in patients with primary polydipsia and emphasizes the basis of the difficulty that may occur clinically in differentiating between patients with primary polydipsia and partial central diabetes insipidus.

Clinical settings and vasopressin function in hyponatraemic children

Hyponatraemia is one of the most common electrolyte abnormalities in hospitalised children. In a prospective study we tested whether hyponatraemia is associated with sustained release of the antidiuretic hormone arginine vasopressin (AVP). Out of 27 children with persistent hyponatremia (serum sodium < 130 mmol/l), 25 had measurable plasma concentrations of AVP [median and quartiles 5.0 pg/ml (1.5-8.3)]. Volume contraction as consequence of sodium loss caused hyponatraemia in 16 patients. Hyponatraemia in the presence of extracellular volume expansion and reduced effective arterial blood volume occurred in 5 patients. Only 3 patients had normovolaemic hyponatraemia (so-called syndrome of inappropriate antidiuretic hormone secretion) and 3 suffered from chronic renal failure. It is concluded that plasma AVP concentration is measurable in most children with hyponatraemia. Non-osmotic stimulation of AVP release and lack of suppression of this hormone is an important pathogenetic mechanism of hyponatraemia in children.

Vasopressin gene expression in rats with experimental cirrhosis

Impaired ability to excrete a water load occurs in a substantial number of patients with advanced cirrhosis and in animals with experimental cirrhosis. The nonosmotic stimulation of arginine vasopressin release from the pituitary has been implicated as an important factor in the abnormal water excretion in patients and animals with cirrhosis. In this study, arginine vasopressin hypothalamic gene expression was studied in cirrhotic rats. Cirrhosis was induced by a combination of phenobarbital treatment in drinking water and weekly intragastric administration of carbon tetrachloride for 13 to 15 wk. Severe cirrhosis was confirmed by morphological analysis and the presence of ascites. Plasma arginine vasopressin was also significantly higher in rats with cirrhosis (control = 1.77 ± 0.16 and cirrhotic rats = 4.14 ± 0.62 pg/ml, n = 9, p < 0.002). Hypothalamic arginine vasopressin messenger RNA was also significantly higher in cirrhotic rats (control = 762.1 ± 132.3 and cirrhotic rats = 1,834.2 ± 271.9 pg/hypothalamus, n = 9, p < 0.005). Pituitary arginine vasopressin content was significantly lowered in cirrhotic rats (control = 3.69 ± 0.98 and cirrhotic rats = 1.57 ± 0.09 μg/pituitary, n = 9, p < 0.05). No difference was seen in hypothalamic arginine vasopressin content between the two groups (control = 4.64 ± 0.34 and cirrhotic rats = 4.23 ± 0.33 ng/hypothalamus, n = 9, NS). Oxytocin messenger RNA in the hypothalamus was also not significantly different between the two groups (control = 8.61 ± 0.68 and cirrhotic rats = 9.33 ± 0.65 unit of density, n = 9, NS). No differences were seen in plasma sodium (control = 145.7 ± 1.62 and cirrhotic rats = 145.9 ± 1.09 mmol/L), plasma osmolality (control = 296.6 ± 2.6 and cirrhotic rats = 297.1 ± 4.2 mOsm/kg H 2O), creatinine clearance and blood urea nitrogen between the two groups. These results therefore provide support for increased hypothalamic biosynthesis and pituitary release of arginine vasopressin in experimental cirrhosis in the rat.

Vasopressin Gene Expression in Rats with Experimental Cirrhosis

Impaired ability to excrete a water load occurs in a substantial number of patients with advanced cirrhosis and in animals with experimental cirrhosis. The nonosmotic stimulation of arginine vasopressin release from the pituitary has been implicated as an important factor in the abnormal water excretion in patients and animals with cirrhosis. In this study, arginine vasopressin hypothalamic gene expression was studied in cirrhotic rats. Cirrhosis was induced by a combination of phenobarbital treatment in drinking water and weekly intragastric administration of carbon tetrachloride for 13 to 15 wk. Severe cirrhosis was confirmed by morphological analysis and the presence of ascites. Plasma arginine vasopressin was also significantly higher in rats with cirrhosis (control = 1.77 +/- 0.16 and cirrhotic rats = 4.14 +/- 0.62 pg/ml, n = 9, p < 0.002). Hypothalamic arginine vasopressin messenger RNA was also significantly higher in cirrhotic rats (control = 762.1 +/- 132.3 and cirrhotic rats = 1,834.2 +/- 271.9 pg/hypothalamus, n = 9, p < 0.005). Pituitary arginine vasopressin content was significantly lowered in cirrhotic rats (control = 3.69 +/- 0.98 and cirrhotic rats = 1.57 +/- 0.09 micrograms/pituitary, n = 9, p < 0.05). No difference was seen in hypothalamic arginine vasopressin content between the two groups (control = 4.64 +/- 0.34 and cirrhotic rats = 4.23 +/- 0.33 ng/hypothalamus, n = 9, NS). Oxytocin messenger RNA in the hypothalamus was also not significantly different between the two groups (control = 8.61 +/- 0.68 and cirrhotic rats = 9.33 +/- 0.65 unit of density, n = 9, NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Pituitary adenylate cyclase-activating polypeptide stimulates arginine vasopressin release in conscious rats.

The effect of pituitary adenylate cyclase-activating polypeptide (PACAP) on arginine vasopressin (AVP) release was investigated in conscious rats. Intracerebroventricular (i.c.v.) administration of PACAP raised the plasma AVP concentration in a dose-dependent manner (50-500 pmol/rat), and the maximum effect was obtained at 5 min after the administration. This AVP-releasing effect was not due to a fall of blood pressure, increase of plasma Na or decrease of plasma volume, all of which are known to stimulate AVP release. PACAP had little effect on blood pressure at a low dose, but at higher doses increased it. Vasoactive intestinal peptide (VIP), which is homologous to PACAP, also raised the plasma AVP concentration by i.c.v. injection. An antagonist for VIP receptor, [Lys, Pro, Arg, Tyr]-VIP inhibited the VIP-induced increase of plasma AVP, but had little effect on PACAP-induced increase of plasma AVP. These results suggest that PACAP stimulates AVP release, via specific receptors which are distinct from VIP receptors.