Increased Plasma Vasopressin Levels Research Articles

Elevated blood pressure follows physiological body-water conservation

Background: Pre-clinical evidence suggests that blood pressure (BP) increase is part of an adaptive physiological body response designed to prevent under-hydration. This idea challenges established thinking that hypertension is caused by initial salt-driven over-hydration. We tested the hypothesis that this alternative view also holds true in humans. Methods: In a mechanistic study, we investigated the interrelation between daily Na+ and water intake, renal solute and water excretion, renal water conservation, and body Na+ balance with BP in 6 healthy men living in a controlled environment for 205 days. In an additional daily-life observational study we investigated the interrelation between BP and adaptive-physiological water and Na+ conservation in 108 Singaporeans. Results: In participants living under controlled conditions, BP increased when urine osmolality was high, and fluid intake or urine volume was low. This BP-increasing water conservation response was not caused by body Na+ retention. Similarly, participants living under daily-life conditions showed a BP-elevating adaptive body water conservation response with increased plasma solute concentration, increased plasma vasopressin levels, and reduced urine volume production due to reduced renal free-water excretion. Participants with higher BP relied on more urea and glucose solutes, but on less Na+ solutes, to maintain their hydration status. Participants with essential hypertension showed more pronounced adaptive-physiological water conservation. None of these hypertension-specific water conservation responses were accompanied by differences in 24-h Na+ excretion. Conclusions: BP increase in humans is part of a systemic body water conservation response that occurs largely independent of body Na+ balance. The Mars500 Salt and Water Homeostasis Project was realized by grant support from the German Federal Ministry for Economics and Technology/DLR Forschung unter Weltraumbedingungen (50WB1624-50WB2024) and the Interdisciplinary Centre for Clinical Research (IZKF Junior Research Group 2), Friedrich-Alexander-University of Erlangen-Nuremberg to JT. The food products were donated by APETITO, Coppenrath und Wiese, ENERVIT, HIPP, Katadyn, Kellogg, Molda, and Unilever. The Sodium Storage in Singaporeans Project was realized with grant support from Duke NUS Medical School (Duke-NUS-KBrFA/2019/0026) to JT. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

N-Methyl-D-aspartate Glutamate Receptor Modulates Cardiovascular and Neuroendocrine Responses Evoked by Hemorrhagic Shock in Rats.

Here, we report the participation of N-methyl-D-aspartate (NMDA) glutamate receptor in the mediation of cardiovascular and circulating vasopressin responses evoked by a hemorrhagic stimulus. In addition, once NMDA receptor activation is a prominent mechanism involved in nitric oxide (NO) synthesis in the brain, we investigated whether control of hemorrhagic shock by NMDA glutamate receptor was followed by changes in NO synthesis in brain supramedullary structures involved in cardiovascular and neuroendocrine control. Thus, we observed that intraperitoneal administration of the selective NMDA glutamate receptor antagonist dizocilpine maleate (MK801, 0.3 mg/kg) delayed and reduced the magnitude of hemorrhage-induced hypotension. Besides, hemorrhage induced a tachycardia response in the posthemorrhage period (i.e., recovery period) in control animals, and systemic treatment with MK801 caused a bradycardia response during hemorrhagic shock. Hemorrhagic stimulus increased plasma vasopressin levels during the recovery period and NMDA receptor antagonism increased concentration of this hormone during both the hemorrhage and postbleeding periods in relation to control animals. Moreover, hemorrhagic shock caused a decrease in NOx levels in the paraventricular nucleus of the hypothalamus (PVN), amygdala, bed nucleus of the stria terminalis (BNST), and ventral periaqueductal gray matter (vPAG). Nevertheless, treatment with MK801 did not affect these effects. Taken together, these results indicate that the NMDA glutamate receptor is involved in the hemorrhagic shock by inhibiting circulating vasopressin release. Our data also suggest a role of the NMDA receptor in tachycardia, but not in the decreased NO synthesis in the brain evoked by hemorrhage.

Alleviation of brain injury by applying TGN-020 in the supraoptic nucleus via inhibiting vasopressin neurons in rats of focal ischemic stroke

AimsTo understand mechanisms underlying vasopressin hypersecretion in stroke and its association with brain injury, we investigated effects of blocking aquaporin 4 (AQP4) in the supraoptic nucleus (SON) on vasopressin neuronal activity and cerebral injuries in male rats of unilateral middle cerebral artery occlusion (MCAO). Main methodsEstablishing MCAO model without or with microinjection of TGN-020 into the SON, performing Western blots and immunohistochemistry and analyzing the expression levels and spatial distribution of functional proteins in the SON and/or the cerebral cortex. Key findingsMCAO increased plasma vasopressin levels, caused neurological damage and increased glycogen synthase kinase 3β (GSK-3β) in the SON and the cortex of MCAO side. In the SON, MCAO significantly increased c-Fos in vasopressin neurons and astrocytic somata in the ventral glial lamina. MCAO significantly reduced glial fibrillary acidic protein (GFAP) and AQP4 around vasopressin neurons, which accompanied separation of GFAP from AQP4. By contrast, blocking AQP4 by microinjection of TGN-020 into the SON blocked MCAO-evoked GSK-3β increase as well as the reduction of AQP4 relative to GFAP around vasopressin neurons in the SON. In the cortex, TGN-020 in the SON also blocked MCAO-evoked increase in GSK-3β while reduced neurological damages. SignificanceThese findings indicate that MCAO disrupts interactions of GFAP with AQP4 in astrocytic processes in the SON, which increases vasopressin neuronal activity. Blocking AQP4 in the SON can block abnormal activation of vasopressin neurons and alleviate ischemic brain injury, which provides novel targets for alleviating ischemic brain injury.

Social isolation rearing-induced anxiety and response to agomelatine in male and female rats: Role of corticosterone, oxytocin, and vasopressin.

Background:The chronobiotic antidepressant, agomelatine, acts via re-entrainment of circadian rhythms. Earlier work has demonstrated late-life anxiety and reduced corticosterone in post-weaning social isolation reared (SIR) rats. Agomelatine was anxiolytic in this model but did not reverse hypocortisolemia. Reduced corticosterone or cortisol (in humans) is well-described in anxiety states, although the anxiolytic-like actions of agomelatine may involve targeting another mechanism. Central oxytocin and vasopressin exert anxiolytic and anxiogenic effects, respectively, and are subject to circadian fluctuation, while also showing sex-dependent differences in response to various challenges.Aims and methods:If corticosterone is less involved in the anxiolytic-like actions of agomelatine in SIR rats, we wondered whether effects on vasopressin and oxytocin may mediate these actions, and whether sex-dependent effects are evident. Anxiety as assessed in the elevated plus maze, as well as plasma vasopressin, oxytocin, and corticosterone were analyzed in social vs SIR animals receiving sub-chronic treatment with vehicle or agomelatine (40 mg/kg/day intraperitoneally at 16:00) for 16 days.Results:Social isolation rearing induced significant anxiety together with increased plasma vasopressin levels, but decreased corticosterone and oxytocin. While corticosterone displayed sex-dependent changes, vasopressin, and oxytocin changes were independent of sex. Agomelatine suppressed anxiety as well as reversed elevated vasopressin in both male and female rats and partially reversed reduced oxytocin in female but not male rats.Conclusion:SIR-associated anxiety later in life involves reduced corticosterone and oxytocin, and elevated vasopressin. The anxiolytic-like effects of agomelatine in SIR rats predominantly involve targeting of elevated vasopressin.

Pressor doses of vasopressin result in only transient elevations in plasma peptide levels

We recently reported that neuronostatin, a novel neuropeptide, biphasically increased mean arterial pressure, first through the activation of the sympathetic nervous system followed by the release of vasopressin. In those experiments, we found that centrally administered neuronostatin increased plasma vasopressin levels only 2–3 times greater than levels observed in saline-treated controls, and that the increase in mean arterial pressure (approximately 15mm Hg) could be blocked by pretreatment with a V1-vasopressin antagonist. Here we report the relationship between two to three fold elevations in plasma vasopressin levels and concomitant changes in mean arterial pressure in conscious, unrestrained male rats. We injected increasing doses of vasopressin (5, 20, and 100ng/kg, intra-arterially) and measured both changes in plasma vasopressin levels and the elevation in mean arterial pressure achieved. At 5-min post injection, plasma levels of vasopressin and mean arterial pressures were similar to those observed following central neuronostatin administration in our earlier study. Thus we conclude that small increases in circulating vasopressin levels can result in significant elevations in mean arterial pressure at least in the conscious rat.

Hypothalamic supraoptic but not paraventricular nucleus is involved in cardiovascular responses to carbachol microinjected into the bed nucleus of stria terminalis of unanesthetized rats

Microinjection of the cholinergic agonist carbachol into the bed nucleus of the stria terminalis (BST) has been reported to cause pressor response in unanesthetized rats, which was shown to be mediated by an acute release of vasopressin into the systemic circulation and followed by baroreflex-mediated bradycardia. In the present study, we tested the possible involvement of the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei in the pressor response evoked by carbachol microinjection into the BST of unanesthetized rats. For this, cardiovascular responses following carbachol (1nmol/100nL) microinjection into the BST were studied before and after PVN or SON pretreatment, either ipsilateral or contralateral in relation to BST microinjection site, with the nonselective neurotransmission blocker cobalt chloride (CoCl2, 1mM/100nL). Carbachol microinjection into the BST evoked pressor response. Moreover, BST treatment with carbachol significantly increased plasma vasopressin levels, thus confirming previous evidences that carbachol microinjection into the BST evokes pressor response due to vasopressin release into the circulation. SON pretreatment with CoCl2, either ipsilateral or contralateral in relation to BST microinjection site, inhibited the pressor response to carbachol microinjection into the BST. However, CoCl2 microinjection into the ipsilateral or contralateral PVN did not affect carbachol-evoked pressor response. In conclusion, our results suggest that pressor response to carbachol microinjection into the BST is mediated by SON magnocellular neurons, without significant involvement of those in the PVN. The results also indicate that responses to carbachol microinjection into the BST are mediated by a neural pathway that depends on the activation of both ipsilateral and contralateral SON.

Effect of repeatedly given CDP-choline on cardiovascular and tissue injury in spinal shock conditions: investigation of the acute phase

The protective effect of CDP-choline in spinal cord transection and the mediation of its cardiovascular effects were investigated. Spinal cords of rats were transected at the T1-T2 levels. CDP-choline (250 mg/kg; intravenous) was administered 2 h and/or 24 h after the injury. Spinal cord transection caused severe tissue damage, decreased mean arterial pressure, heart rate, plasma adrenaline, and noradrenaline but increased plasma vasopressin levels. Repeated CDP-choline treatment attenuated the degree of tissue injury. Administration of CDP-choline at 2 h after transection transiently increased blood pressure and decreased heart rate, while it produced a small decrease in blood pressure and heart rate when it was given at 24 h. Plasma adrenaline levels were higher in the group where CDP-choline was given repeatedly. Plasma noradrenaline and vasopressin levels did not change additionally after CDP-choline injections in all groups. In order to determine if CDP-choline attenuates the oxidative injury induced by transection, we measured blood superoxide dismutase, glutathione peroxidase activity and malondialdehyde levels. Repeated CDP-choline administration decreased blood superoxide dismutase and glutathione peroxidase activity without any effect on malondialdehyde levels. Data indicate that repeated intravenous CDP-choline treatment prevents tissue damage in spinal shock conditions in the acute phase. The cardiovascular effects of the drug do not seem to be responsible for this protection but the drug-induced attenuation of the oxidative stress may play a role.

Pressor response to fluid resuscitation in endotoxic shock: Involvement of vasopressin*

To investigate the effects of fluid resuscitation administration on vasopressin secretion and its association with pressor response in endotoxic shock during a period of inappropriately low vasopressin secretion. Prospective, controlled experiment. Animal basic science laboratory. Male Wistar rats, weighing 250 to 300 grams. Rats received lipopolysaccharide (2 mg/kg, intravenous) and had their mean arterial pressure monitored during the next 4 hrs. Subsequently, the animals were assigned randomly to one of seven groups (n = 6 per group) that differed in the composition or volume of the resuscitation fluid administered: control group (no fluid administered); isotonic saline solution (0.9% NaCl; 4 mL/kg); hypertonic saline solution (7.5% NaCl; 4 mL/kg); 0.9% NaCl in 6% hydroxyethyl starch 450/0.7 (4, 8, or 16 mL/kg); or 7.5% NaCl in 6% hydroxyethyl starch 450/0.7 (4 mL/kg). Blood pressure was lower in the lipopolysaccharide-treated group. Administration of 0.9% NaCl in 6% hydroxyethyl starch 450/0.7 did not change mean arterial pressure, but reduced vasopressin plasma levels at a dose of 16 mL/kg. Hypertonic saline solution or 7.5% NaCl in 6% hydroxyethyl starch 450/0.7 administration was followed by an immediate recovery of blood pressure and also by an increase in plasma vasopressin levels when compared to isotonic saline solution. The vasopressin V1 receptor antagonist (10 microg/kg, intravenous, 5 min before infusion) completely blunted the increase in mean arterial pressure induced by hypertonic saline solution or 7.5% NaCl in 6% hydroxyethyl starch 450/0.7 in endotoxemic rats. Isotonic blood volume expansion reduced vasopressin plasma levels. Furthermore, the subsequent release of vasopressin is essential for the pressor response caused by hypertonic fluid infusion during endotoxic shock.

REGULATION OF RENAL AQUAPORINS AND SALT TRANSPORTERS IN LOW SODIUM DIET RATS WITH EXPERIMENTALLY INDUCED HEART FAILURE

Heart failure (HF) is a common complication to myocardial infarction (MI) and is associated with increased plasma vasopressin levels and renal AQP2 protein abundance as well as sodium and water retention. Thus reduced sodium intake is often recommended to patients with HF. To examine the underlying renal molecular mechanisms in low‐output HF, male rats were subjected to ligation of the left anterior descending artery. The following MI and HF were confirmed with echocardiography at day seven. During the last seven days of experiment all the rats were fed a low sodium diet and treated with dDAVP (20 ng/h s.c.) or vehicle. The rats were divided into four groups: Sham (n=6); Sham+dDAVP (n=6); HF (n=5), HF+dDAVP (n=6). In dDAVP treated groups the protein abundance of AQP2, p(S256)‐AQP2 and renal sodium transporters increased. Surprisingly vehicle‐treated HF rats failed to increase or even decreased protein abundance of water and sodium transporters, the finding being most profound in inner medulla. In conclusion, the findings support that sodium restriction may be important as a powerful clinical tool against renal water and sodium retention associated with low‐output HF.Danish Medical Research Council

Interaction of vasopressin infusion, corticosteroid treatment, and mortality of septic shock*

Vasopressin and corticosteroids are often added to support cardiovascular dysfunction in patients who have septic shock that is nonresponsive to fluid resuscitation and norepinephrine infusion. However, it is unknown whether vasopressin treatment interacts with corticosteroid treatment. Post hoc substudy of a multicenter randomized blinded controlled trial of vasopressin vs. norepinephrine in septic shock. Twenty-seven Intensive Care Units in Canada, Australia, and the United States. : Seven hundred and seventy-nine patients who had septic shock and were ongoing hypotension requiring at least 5 microg/min of norepinephrine infusion for 6 hours. Patients were randomized to blinded vasopressin (0.01-0.03 units/min) or norepinephrine (5-15 microg/min) infusion added to open-label vasopressors. Corticosteroids were given according to clinical judgment at any time in the 28-day postrandomization period. The primary end point was 28-day mortality. We tested for interaction between vasopressin treatment and corticosteroid treatment using logistic regression. Secondary end points were organ dysfunction, use of open-label vasopressors and vasopressin levels. There was a statistically significant interaction between vasopressin infusion and corticosteroid treatment (p = 0.008). In patients who had septic shock and were also treated with corticosteroids, vasopressin, compared to norepinephrine, was associated with significantly decreased mortality (35.9% vs. 44.7%, respectively, p = 0.03). In contrast, in patients who did not receive corticosteroids, vasopressin was associated with increased mortality compared with norepinephrine (33.7% vs. 21.3%, respectively, p = 0.06). In patients who received vasopressin infusion, use of corticosteroids significantly increased plasma vasopressin levels by 33% at 6 hours (p = 0.006) to 67% at 24 hours (p = 0.025) compared with patients who did not receive corticosteroids. There is a statistically significant interaction between vasopressin and corticosteroids. The combination of low-dose vasopressin and corticosteroids was associated with decreased mortality and organ dysfunction compared with norepinephrine and corticosteroids.

VASOPRESSIN MEDIATES THE PRESSOR EFFECT OF HYPERTONIC SALINE SOLUTION IN ENDOTOXIC SHOCK

The administration of lipopolysaccharide (LPS) to experimental animals results in a septic shock-like syndrome characterized by hypotension, and the hemodynamic management includes the restoration of adequate tissue perfusion by administration of resuscitation fluids to achieve an effective circulating volume. In the present study, we sought to investigate the effects of hypertonic saline solution administration on vasopressin secretion and mean arterial pressure in endotoxic shock. The pressor response to isotonic saline solution (0.9% sodium chloride) or hypertonic saline (7.5% sodium chloride, 4 mL/kg i.v.) was evaluated 4 h after LPS (1.5 mg/kg) administration. At this moment, plasma vasopressin did not differ from control; however, the blood pressure was lower in the LPS-treated group. The hypertonic saline administration was followed by an immediate recovery of blood pressure and also by an increase in plasma vasopressin levels compared with isotonic saline solution. The vasopressin V1 receptor antagonist (10 microg/kg, i.v., 5 min before infusion) blocked the pressor response to hypertonic saline solution. These data suggest that the recovery of blood pressure after hypertonic saline solution administration during endotoxic shock is mediated by vasopressin secretion.

Cardiovascular effects of l-glutamate microinjection in the supraoptic nucleus of unanaesthetized rats

We report on the cardiovascular effects of l-glutamate ( l-glu) microinjection in the hypothalamic supraoptic nucleus (SON) as well as possible receptor and mechanisms involved. Microinjection of l-glu in 100 nL in the SON caused dose-related pressor and bradycardic responses in unanesthetized rats. Responses were markedly reduced in urethane-anesthetized rats. The response to l-glu 10 nmol was blocked by local pretreatment with 2 nmol of the non-NMDA-receptors antagonist NBQX and not affected by 2 nmol of the selective NMDA-receptor antagonist LY 235959, suggesting that non-NMDA receptors mediate these responses. The pressor and bradycardic response to l-glu was potentiated by intravenous pretreatment with the ganglion blocker pentolinium and was blocked by intravenous pretreatment with the V 1-vasopressin receptor antagonist dTyr(CH 2) 5(Me)AVP, suggesting involvement of circulating vasopressin in this response. Additionally l-glu microinjection into the SON increased plasma vasopressin levels (control: 1.3 ± 0.2 pg/mL, n = 6; l-glu: 14.7 ± 2.3 pg/mL, n = 6). In conclusion the results suggest that pressor responses to SON microinjection of l-glu are caused by activation of non-NMDA glutamate receptors and mediated by vasopressin release into systemic circulation.

Pkd1 Haploinsufficiency Is Associated with Altered Osmoregulation and Calcium Signaling in Collecting Duct

ADPKD patients have an impaired urinary concentrating capacity despite increased plasma vasopressin levels. A defective vasopressin-2 receptor (V2R) pathway is involved in the progression of cystogenesis in animal models of PKD. We used a non-cystic mouse model to investigate the effect of Pkd1 haploinsufficiency on water handling and V2R signaling prior to cystogenesis and renal failure. The Pkd1+/− and Pkd1+/+ mice had normal renal function and histology. At baseline Pkd1+/− mice showed a 3-fold decrease in urinary output with significantly higher urine osmolality and lower plasma osmolality. The Pkd1+/− mice had a decreased aquaretic response to water load and selective V2R blockade, and showing an abnormal release of AVP in the plasma, irrespective of the hypo-osmolality. The cAMP levels in kidney lysates and urine were similar in both groups, as were the transcription levels of aquaporin-2 (AQP2), V2R and cAMP-dependent mediators in kidney (real-time qPCR). However, immunoblotting showed a strong upregulation of AQP2 and phosphorylated (Ser256) AQP2 in Pkd1+/− kidneys, with an increased AQP2 targeting in the apical membrane of the collecting duct (CD) principal cells evidenced by immuno-electron microscopy. Further studies showed a significantly lower basal [Ca2+]i in isolated inner medullary CDs of Pkd1+/− mice, as well as a significant upregulation of phosphorylated (Ser188) RhoA coupled to downregulated RhoA, pointing to a less stimulated state of the apical V1a and calcium-sensing receptors. These data indicate that, in absence of renal failure or cystic changes, Pkd1 haploinsufficiency is associated with abnormal release of AVP and inappropriate antidiuresis due to the plasma membrane recruitment of p-AQP2 in CD cells. The effect of AVP is potentialized downstream of V2R, in association with low [Ca2+]i and increased p-RhoA in CD cells.

Polycystic kidney disease: genes, proteins, animal models, disease mechanisms and therapeutic opportunities

An increased understanding of the genetic, molecular and cellular mechanisms responsible for the development of polycystic kidney disease has laid out the foundation for the development of rational therapies. Many animal models where these therapies can be tested are currently available. This review summarizes the rationale for these treatments, the results of preclinical trials and the prospects for clinical trials, some already in early phases of implementation.

Effects of i.c.v. losartan on the angiotensin II-mediated vasopressin release and hypothalamic fos expression in near-term ovine fetuses

Our previous studies have shown that central administration of angiotensin (ANG II) causes arginine vasopressin (AVP) release in the fetus at 70–90% gestation. This is evidence that the hypothalamic-neurohypophysial system is relatively mature before birth. However, few data exist regarding central ANG receptor mechanisms-mediated AVP response during fetal life. To determine roles of brain ANG receptor subtypes in this response, AT 1 and AT 2 receptor antagonists, losartan and PD123319, were investigated in the brain in chronically prepared ovine fetuses at the last third of gestation. Application of losartan intracerebroventricularly (i.c.v.) at 0.5 mg/kg suppressed central ANG II-stimulated plasma AVP release. Losartan at 5 mg/kg (i.c.v.) demonstrated a significant enhancement of AVP increase to i.c.v. ANG II. Associated with the increase of plasma vasopressin levels, c-fos expression in the hypothalamic neurons was significantly different between the low and high doses of losartan. The low dose losartan markedly reduced the dual immunoreactivity for FOS and AVP in the supraoptic nuclei and paraventricular nuclei after i.c.v. ANG II, whereas the high dose losartan together with ANG II, significantly increased the co-localization of positive FOS in the AVP-containing neurons than that induced by i.c.v. ANG II alone. Central ANG II induced fetal plasma vasopressin increase was not altered by PD123319. The data suggest that losartan in the fetal brain has remarkably different effects based on the doses administrated on central ANG II-related neuroendocrine effects at the late gestation, and that the AT 1 mechanism is critical in the regulation of fetal body fluid homeostasis related to plasma AVP levels.

Centrally injected CDP-choline increases plasma vasopressin levels by central cholinergic activation.

In the present study, both the effects of intracerebroventricular (i.c.v.) injection of cytidine-5'-diphosphate choline (CDP-choline) on plasma vasopressin levels and the choline involvement of these effects were investigated. I.c.v. administration of CDP-choline (0.5, 1.0 and 2.0 micromol) increased plasma vasopressin levels dose- and time-dependently. I.c.v. injection of equimolar dose of choline (1 micromol) produced similar vasopressin response. However equimolar dose of cytidine (1 micromol; i.c.v.), the other hydrolysis product of CDP-choline, did not affect plasma vasopressin levels. Pretreatment of rats with hemicholinium-3, neuronal high affinity choline uptake inhibitor (20 microg; i.c.v.) blocked the vasopressin response to i.c.v. CDP-choline (1 micromol). Pretreatment of rats with mecamylamine (50 microg; i.c.v.), a nonselective nicotinic receptor antagonist, abolished the increase in plasma vasopressin induced by CDP-choline while atropine (10 microg; i.c.v.), nonselective muscarinic receptor antagonist, failed to change the response. In conclusion, intracerebroventricularly injected CDP-choline can increase plasma vasopressin levels by activating central nicotinic cholinergic receptors through the activation of presynaptic cholinergic mechanisms.

Intracerebroventricular choline increases plasma vasopressin and augments plasma vasopressin response to osmotic stimulation and hemorrhage

Intracerebroventricular (i.c.v.) injection of choline (50–150 μg), a precursor of the neurotransmitter acetylcholine, produced a time-and dose-dependent increase in plasma vasopressin levels in conscious, freely moving rats. The increase in plasma vasopressin in response to i.c.v. choline (150 μg) was inhibited by pretreatment with the nicotinic receptor antagonist, mecamylamine (50 μg; i.c.v.), but not by the muscarinic receptor antagonist, atropine (10 μg; i.c.v). The choline-induced rise in plasma vasopressin levels was greatly attenuated by hemicholinium-3 (HC-3; 20 μg; i.c.v.), a neuronal choline uptake inhibitor. Choline (50 or 150 μg; i.c.v.) produced a much greater increase in plasma vasopressin levels in osmotically stimulated or hemorrhaged rats than in normal rats. Choline (150 μg; i.c.v.) also enhanced plasma vasopressin response to graded hemorrhage; the enhancing effect of choline was also attenuated by HC-3 (20 μg; i.c.v.). Choline and acetylcholine concentrations in hypothalamic dialysates increased significantly following i.c.v. injection of choline (150 μg). It is concluded that choline increases plasma vasopressin levels by stimulating central nicotinic receptors indirectly, through the enhancement of acetylcholine synthesis and release, and augments the ability of osmotic stimulations or hemorrhage to stimulate vasopressin release.

Hypothalamic Pituitary Adrenal Axis and Hypothalamic–Neurohypophyseal Responsiveness in Water-Deprived Rats

The differential effects of osmotic stimulation on magnocellular and parvocellular hypothalamic neurons were studied by analysis of corticotropin-releasing hormone (CRH) and vasopressin (VP) expression in controls and 48-h water-deprived rats subjected to either restraint for 1 h or a single lipopolysaccharide injection (250 μg/100 g). Water deprivation reduced basal CRH mRNA levels but the increments following 4 h of restraint or 6 h lipopolysaccharide (LPS) injection were similar to those in controls. In contrast, water deprivation had no effect on basal VP heteronuclear RNA (hnRNA) and mRNA levels in parvocellular neurons, but responses to restraint or LPS injection were reduced. VP expression in magnocellular paraventricular and supraoptic nuclei, and plasma sodium and vasopressin were higher in water-deprived rats, changes which were unaffected by restraint. LPS injection reduced VP mRNA but not hnRNA levels in magnocellular neurons and increased plasma vasopressin levels only in water-deprived rats independently of changes in plasma sodium. This was accompanied by an increase in vasopressin mRNA content in the posterior pituitary. The data show that the blunted ACTH responses to acute stress during chronic osmotic stimulation are correlated with the inability of parvocellular neurons to increase VP rather than CRH expression. In addition, LPS-induced endotoxemia causes disturbances of the magnocellular vasopressinergic system with an unexpected potentiation of osmotic simulated VP secretion. The lack of increase in VP transcription after LPS and changes in VP mRNA distribution suggest that endotoxemia affect the secretory process at the levels of the neurohypophyseal axon terminal.

Neural mechanisms subserving central angiotensinergic influences on plasma renin in sheep.

The mechanisms and brain regions subserving the suppression of plasma renin concentration caused by intracerebroventricular (ICV) infusion of angiotensin II were studied in sodium-depleted sheep. Infusion of angiotensin II (3 microg/h for 1 hour) into the lateral ventricle reduced plasma renin from 4.3+/-0.4 to 1.6+/-0.2 pmol angiotensin I/mL per hour at 1 hour after the commencement of infusion. This change persisted for at least another 90 minutes and was blocked by concomitant ICV infusion of the AT(1) antagonist losartan (1 mg/h). Arterial pressure did not change, but plasma vasopressin secretion was increased. ICV infusion of losartan (1 mg/h) significantly increased plasma renin in sodium-depleted sheep. The reduction of plasma renin concentration in response to either ICV angiotensin II or hypertonic NaCl (0.75 mol/L at 1 mL/h) and the increase in response to ICV losartan was prevented in sheep in which the lamina terminalis of the brain had been ablated. Lesions in the median eminence (MEL), which blocked the increased plasma vasopressin levels, did not prevent suppression of plasma renin in response to ICV angiotensin II. However, bilateral renal denervation largely blocked this inhibition of plasma renin concentration but not the increased plasma renin resulting from ICV infusion of losartan in sodium-depleted sheep. The results show that AT(1) receptors, probably located in the lamina terminalis, mediate a central inhibitory influence of angiotensin II on renin secretion. This inhibition of renin release is probably due to a reduction in activity of renal sympathetic nerves innervating the juxtaglomerular apparatus of the kidney.

Collecting duct (Na+/K+)-ATPase activity is correlated with urinary sodium excretion in rat nephrotic syndromes.

In puromycin aminonucleoside (PAN)-treated nephrotic rats, sodium retention is associated with increased (Na+/K+)-ATPase activity in the cortical collecting ducts (CCD). This study was undertaken to determine whether stimulation of (Na+/K+)-ATPase in the CCD is a feature of other experimental nephrotic syndromes, whether it might be responsible for renal sodium retention, and whether it is mediated by increased plasma vasopressin levels or activation of calcineurin. For this purpose, the time courses of urinary excretion of sodium and protein, sodium balance, ascites, and (Na+/K+)-ATPase activities in microdissected CCD were studied in rats with PAN or adriamycin nephrosis or HgCl2 nephropathy. The roles of vasopressin and calcineurin in PAN nephrosis were evaluated by measuring these parameters in Brattleboro rats and in rats treated with cyclosporin or tacrolimus. Despite different patterns of changes in urinary sodium and protein excretion in the three nephrotic syndrome models, there was a linear relationship between CCD (Na+/K+)-ATPase activities and sodium excretion in all three cases. The results also indicated that there was no correlation between proteinuria and sodium retention, but ascites was present only when proteinuria was associated with marked reduction of sodium excretion. Finally, the lack of vasopressin in Brattleboro rats or the inhibition of calcineurin by administration of either cyclosporin or tacrolimus did not prevent development of the nephrotic syndrome in PAN-treated rats or stimulation of CCD (Na+/K+)-ATPase. It is concluded that stimulation of Na(+/K+)-ATPase in the CCD of nephrotic rats might be responsible for sodium retention and that this phenomenon is independent of proteinuria and vasopressin and calcineurin activities.