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PubMed1990

The role of arginine vasopressin in alcohol tolerance.

Administration of the neuropeptide, arginine vasopressin, to animals that have acquired functional tolerance to ethanol will maintain such tolerance, even in the absence of further ethanol ingestion by the animals. In mice, this action of the peptide is mediated by central nervous system V1 receptors and requires intact brain noradrenergic systems. Autoradiographic studies have shown that some V1 receptors are localized presynaptically on catecholaminergic neuronal terminals in the mouse lateral septum, suggesting that vasopressin may act via modulation of catecholamine release. In addition, vasopressin has been found to increase mRNA levels for the proto-oncogene, c-fos, in septum and hippocampus, possibly by an action at postsynaptic receptors. Expression of c-fos, which has been hypothesized to play a role in central nervous system neuroadaptation, could transform short-term actions of vasopressin into long-term effects on ethanol tolerance. Studies with vasopressin antagonists indicate that the endogenous peptide influences tolerance, and therefore the effect of chronic ethanol ingestion on vasopressin synthesis and release was studied. In mice and rats, hypothalamic vasopressin mRNA is decreased by chronic ethanol exposure, although effects on plasma vasopressin levels differ in the two species. The effect of ethanol on extrahypothalamic vasopressin synthesis in brain is under investigation. The results suggest mechanisms by which vasopressin can produce long-term changes in central nervous system function, and provide evidence for a disturbance of vasopressin regulation during chronic ethanol ingestion.

Alcohol Drinking↗
PubMed1987

Identification and characterization of vascular (V1) vasopressin receptors of an established smooth muscle cell line.

We report the identification and characterization of specific vasopressin-binding sites on intact cells and membranes of the established vascular smooth muscle cell line A-10, the fate of vasopressin associated with the cells, the role of guanine nucleotides in the regulation of the affinity of the vasopressin-binding sites, and the determination of the vasopressin receptor subtype. We have found specific vasopressin-binding sites on intact cells in monolayer (110,000 sites per cell during log growth and 60,000 sites per cell in stationary culture) with a KD of 6 nM at 37 degrees. After incubation of [3H]-8-arginine vasopressin ([3H]AVP) and cells for less than 20 min, cell-associated AVP was intact; with longer incubation times, AVP was progressively degraded. The major metabolites included phenylalanine and a fraction that eluted from a C18 reverse phase high performance liquid chromatography column between AVP and 8-arginine, 9-desglycinamide vasopressin. Extensive degradation also occurred when AVP was allowed to dissociate from the cells. With increased time of incubation, the amount of specifically bound AVP that could dissociate decreased, suggesting receptor-mediated endocytosis. In saturation equilibrium binding experiments with plasma membranes, two affinity states with KD of 0.7 nM and 379 nM were observed. The number of high affinity binding sites was similar to the number of receptors found on intact cells. Guanosine 5'-(beta,gamma-imido)triphosphate decreased vasopressin binding to the high affinity sites and did not significantly affect the low affinity sites. Competition binding experiments indicated that the vasopressin-binding sites of A-10 cells belong to the vascular V1 receptor subtype. We conclude that the established vascular smooth muscle cell line A-10 expressed vasopressin receptors of the vascular V1 subtype. Vasopressin bound to the receptors reversibly, but could also be degraded by the cells presumably after receptor-mediated endocytosis. The receptors might exist in different affinity states; guanosine 5'-(beta,gamma-imido)triphosphate decreased the affinity of the high affinity binding state.

Animals↗
PubMed1985

Antidiuretic hormone antagonists and aquaresis in dogs: different vasopressin sensitivity and antagonist potency in renal cortex and papilla.

To understand the molecular mechanism of action of the novel class of diuretic agents, the antidiuretic hormone antagonists ["aquaretics" (specific water-losing activity as caused by vasopressin antagonists, as distinguished from the saluresis of conventional diuretics)], in the dog studies were made of the properties of the vasopressin-responsive adenylate cyclase system and the antagonist potencies of the vasopressin analogs [1-(beta-mercapto-beta, beta-cyclopentamethylenepropionic acid), 2-(O-ethyl)tyrosine,4-valine,8-arginine]vasopressin; [1-(beta-mercapto-beta-mercapto-beta, beta-cyclopentamethylenepropionic acid), 2-D-phenylalanine,4-valine,8-arginine]vasopressin; and [1-(beta-mercapto-beta, beta-cyclopenta-methylenepropionic acid), 2-D-(O-ethyl)tyrosine,4-valine,8-arginine]vasopressin (SK&F 100398, 101071 and 101498, respectively) using plasma membranes prepared from cortex, medulla and papilla of dog kidney. It was observed that the greatest sensitivity for vasopressin was in the papilla (concentration of 8-arginine vasopressin required for 50% activation of adenylate cyclase [Kact] was 2.0 X 10(-9)M, 1.1 X 10(-9)M and 5.1 X 10(-10) M in the cortex, medulla and papilla, respectively). The addition of 10(-5)M GTP did not alter the Kact of the cortex but enhanced 10-fold the vasopressin sensitivity of the papilla to 5.2 X 10(-11) M. The vasopressin analogs were competitive antagonists of vasopressin-stimulated adenylate cyclase of cortex and papilla with the greatest potency for the papillary enzyme (Ki in papilla was 3.6 X 10(-9)M, 4.6 X 10(-9)M and 1.0 X 10(-9)M for SK&F 100398, 101071 and 101498, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMedDate not supplied

Pharmacokinetic-hemodynamic interactions between vasopressin and nitroglycerin: comparison between intravenous and cutaneous routes of nitrate delivery.

Addition of nitroglycerin (NTG) improves the hemodynamic response to vasopressin and may thus be useful in the treatment of gastrointestinal hemorrhage. We studied in the rat the influence of vasopressin on the disposition of a constant intravenous infusion of NTG and the cutaneous absorption of NTG ointment. The effect of NTG on the pharmacokinetics of vasopressin was also determined. Animals were divided into four groups: control, NTG, vasopressin and vasopressin + NTG. Infusions (or ointments) were maintained for 70 min; cardiac output and regional blood flows were determined with the microsphere technique. Both intravenous and cutaneous NTG resulted in similar hemodynamic responses. Vasopressin caused generalized vasoconstriction, while the addition of NTG reversed the deleterious systemic hemodynamic effects of vasopressin. Addition of vasopressin to NTG did not alter NTG systemic clearance nor did NTG affect vasopressin clearance. Of note, the systemic clearance of NTG was directly correlated with the cardiac output (r = 0.804), supporting a model of NTG distribution where blood vessels and/or extrahepatic tissues are the site of elimination of the drug. The marked reduction in skin blood flow by vasopressin did not decrease the steady-state plasma concentration of NTG nor the estimated cutaneous absorption rate of NTG ointment, indicating that cutaneous blood flow is not an important determinant in the absorption of NTG ointment. The skin is an appropriate route of delivery for NTG when combined with vasopressin.

Animals↗
PubMed1993

Vasopressin induction of long-lasting potentiation of synaptic transmission in the dentate gyrus.

Vasopressin receptors are present in both the developing and mature dentate gyrus of the rat brain and are of the V1 vasopressor type. Because vasopressin has been shown to influence memory function when injected into the dentate gyrus, the influence of this peptide on an electrophysiological model of learning and memory using the field excitatory postsynaptic potential (EPSP) of the dentate gyrus was investigated. Results of these studies showed that nanomolar concentrations of [Arg8]-vasopressin induced a prolonged increase in the amplitude and slope of the evoked population response in the presence of 1.5 mM calcium. Moreover, the expression of the vasopressin-induced potentiation of the EPSP persisted following removal of vasopressin from the perfusion medium. The vasopressin-induced sustained increase has been termed long-term vasopressin potentiation (LTVP). The closely related neuropeptide oxytocin had no effect upon the EPSP of the dentate gyrus. Preincubation of hippocampal slices in a selective V1 antagonist blocked the expression of LTVP. The ability of the V1 antagonist to block LTVP demonstrates that the potentiation induced by vasopressin is receptor-specific. In the presence of 2.5 mM calcium, the effect of vasopressin was opposite to that observed in 1.5 mM calcium. Under the conditions of 2.5 calcium, vasopressin induced a prolonged depression in the amplitude and slope of the EPSP. Expression of both potentiation and depression appeared within 5 minutes of application and persisted for the length of the observation, 60 minutes. These experiments demonstrate that vasopressin can induce long-lasting changes in the excitability of dentate gyrus neurons that are both calcium-dependent and receptor-specific.

Animals↗
PubMed1988

Vasopressin: a model for the study of effects of additives on the oral and rectal administration of peptide drugs.

We previously observed, using a relatively primitive assay, that small oral doses (on the order of 1 microgram = 1 nmol = 1000 pmol per rat) of vasopressin can produce antidiuresis in hydrated rats, and that the oral activity was enhanced by simultaneous administration of an inhibitor of intestinal proteolysis. A more sensitive semi-automated computer-linked apparatus was used to conveniently and quickly compare the antidiuretic activities of the two natural and one synthetic vasopressin peptides by several routes of administration. (The approximate dose in pmol that resulted in a 50% decrease in urine flow is indicated in square brackets.) Intravenous lysine vasopressin was used as the benchmark dose [5]. Arginine and lysine vasopressin [3500], and the synthetic analogue, 1-deamino-8-D-arginine vasopressin (DDAVP) [20], were active by oral administration. The oral activities of arginine and lysine vasopressin were always enhanced by the simultaneous administration of aprotinin [1000], a natural inhibitor of trypsin; the effect of aprotinin on the oral activity of DDAVP was inconsistent. The vasopressins were more active when administered by the rectum: arginine vasopressin [20] and DDAVP [10]. The rectal activities of the peptides were increased by the absorption adjuvant, 5-methoxysalicylate (arginine vasopressin [10]; DDAVP [0.5]). The vasopressin peptides were also delivered by mouth in an impermeable coating of an azoaromatic cross-linked polymer, which is degraded by bacteria in the colon, to release the peptides in the upper colon for absorption (lysine vasopressin [525]).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed2002

Cardiac necrosis markers associated with low nitric oxide levels in the plasma of rabbits after treatment with vasopressin: protective effects of nitroglycerin administration.

It has been reported that the administration of vasopressin induces myocardial ischaemia in rats, which causes electrocardiographic ST segment alterations according to many authors. But rat electrocardiogram (ECG) lacks ST segment. Consequently it appears important to study the effects of vasopressin in rabbits, which show ST segment present in the ECG. Since cardiac necrosis markers are released in the plasma of humans with myocardial infarction, as well as in a variety of experimental models of myocardial necrosis, it is possible that the same may occur in rabbits with myocardial ischaemia induced by vasopressin. The main aim of this study was to investigate whether the administration of vasopressin causes the appearance of specific myocardial necrosis markers, such as cardiac troponin I, myoglobin or creatine kinase MB (CK MB) in rabbits in the presence or absence of modified ECG profile, and to also verify whether these markers are associated with the alterations in some coagulation parameters, that are known to be induced by vasopressin. As the effects of vasopressin are counteracted by nitric oxide (NO), another aim was to verify whether vasopressin also affects plasma NO levels and whether the administration of a NO donor can reverse these effects. Vasopressin was administered to rabbits and caused ischaemic alterations such as electrocardiographic changes, and significantly increased the levels of plasma cardiac necrosis markers (c-troponin I, myoglobin and CK MB). It also elevated diastolic blood pressure (BP), lowered heart rate (HR), increased procoagulation activity, and lowered plasma NO levels. The appearance of heart necrosis, demonstrated by plasma cardiac necrosis markers in the animals receiving vasopressin, was attributed to a drug-induced increase in vasoconstriction and coagulation activity. The intense vasoconstriction and thrombosis may lead to endothelium necrosis and a consequent drop in NO production. The administration of the NO donor nitroglycerin (NG) in the vasopressin treated animals restored NO values, and was capable of preventing the appearance of the plasma cardiac necrosis markers and altered coagulation values. The protective activity of NG was attributed to NO release, which lowers BP values and counteracts coagulation activity in vasopressin-treated animals. The described procedure may also be proposed for the study of early ischaemic myocardial lesions and the screening of NO donors preventing myocardial damage.

Animals↗
PubMed1995

[Arg8]vasopressin-induced responses of the human isolated coronary artery: effects of non-peptide receptor antagonists.

Contractions induced by [Arg8]vasopressin (vasopressin) and the effect of nonpeptide vasopressin receptor antagonists were studied in the human isolated coronary artery. Vasopressin induced contraction of coronary artery segments with a high pD2 (9.25) but a low Emax (11.8% of the response to 100 mM K+). This response was not affected by removal of the endothelium. Contraction was antagonized by the vasopressin V1 receptor antagonist SR 49059 ((2S) 1-[(2R 3S)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxybenzene- sulfonyl)-3-hydroxy-2,3-dihydro-1H-indole-2-carbonyl]-pyrrolidine-2- carboxamide) (pA2: 9.76). OPC-31260 ([5-dimethylamino-1-(4-(2-methylbenzoylamino)benzoyl)-2,3,4,5-tetr ahydro-1H- benzazepine]: vasopressin V2 receptor antagonist) and OPC-21268 (1-(1-[4-(3-acetylaminopropoxy) benzoyl]-4-piperidyl)-3,4- dihydro-2(1H)-quinolinone: reported vasopressin V1 receptor antagonist) were less potent antagonists of vasopressin-induced contractions (pA2: 7.31 and 5.6, respectively). The antagonist potency order (SR 49059 > OPC-31260 > OPC-21268) corresponds to the reported affinity order for the human cloned vasopressin V1 receptor. Therefore, the vasopressin V1 receptor antagonist SR 49059, but not OPC-21268, appears to be an appropriate tool to investigate further the role of vasopressin in pathological processes involving coronary vasoconstriction in humans.

Adolescent↗
PubMed1985

Vasopressin- and neurophysin-immunoreactive neurons in the septal region, medial amygdala and locus coeruleus in colchicine-treated rats.

The distribution and morphology of neurons containing vasopressin, oxytocin and their associated neurophysins were examined immunohistochemically in rats given intracerebroventricular injections of colchicine. Under these conditions, numerous neurons containing vasopressin and neurophysin were found in several brain areas in addition to those previously described in the hypothalamus. Individual parvocellular vasopressin neurons were scattered in the medial and lateral septum and vertical limb of the nucleus of the diagonal band, while a large number of such neurons were found throughout both the bed nucleus of the stria terminals and the dorsal portion of the medial amygdala. In addition a small cluster of parvocellular vasopressin neurons was present adjacent to the top of the third ventricle in the posterior dorsal hypothalamic area and a number of such neurons were found in the ventral locus coeruleus and sub coeruleus. The mean diameters of these parvocellular vasopressin neurons ranged from 16.6 to 19.8 micron in the different regions, in contrast to the 25.4 micron mean diameter of hypothalamic magnocellular vasopressin neurons, or the 13.7 micron mean diameter of parvocellular vasopressin neurons in the suprachiasmatic nucleus. No vasopressin neurons were found in other brain and spinal cord regions under the conditions used in this study, although all regions were examined. No oxytocin neurons other than those previously described in the hypothalamus and immediately contiguous regions were found. Measurement of the mean diameter of oxytocin neurons showed that neurons in the caudal paraventricular nucleus were clearly smaller (18.9 micron) than magnocellular oxytocin neurons (24.8 micron) in other parts of the hypothalamus. These parvocellular oxytocin neurons with experimentally documented central connections were similar in both size and appearance to the parvocellular vasopressin neurons seen after colchicine treatment, which are potential sources of certain central vasopressin pathways. These findings indicate that there are at least two types of oxytocin neurons in the hypothalamus and several types of vasopressin neurons in a variety of different areas in the brain, many of which are outside of the hypothalamus.

Amygdala↗
PubMed1996

Arginine vasopressin release by acetylcholine or norepinephrine: region-specific and cytokine-specific regulation.

Interferon-alpha and transforming growth factor-beta 1 have been detected in the brain, suggesting their possible regulatory functions. In the present study, we evaluated the effects of these cytokines on the in vitro release of arginine vasopressin, previously reported to be sensitive to neurotransmitters such as acetylcholine, norepinephrine, and corticotropin releasing hormone as well as to cytokines interleukin-1 and interleukin-2. Interferon-alpha was found to enhance arginine vasopressin release from both hypothalamus and amygdala, as was dibutyryl cyclic GMP. Blockade of nitric oxide synthase antagonized the interferon-alpha induced arginine vasopressin release from the amygdala but not from the hypothalamus. Transforming growth factor-beta 1 had no effect on basal release of arginine vasopressin, nor on the arginine vasopressin-release induced by interferon-alpha, interleukin-2 or norepinephrine, but selectively blocked the acetylcholine-induced release in both hypothalamus and amygdala. When the release of arginine vasopressin induced by interferon-alpha, interleukin-2, acetylcholine and norepinephrine was probed with inhibitors of guanylate cyclase, the interactions exhibited regional selectivity: neither the interleukin-2-induced arginine vasopressin release from hypothalamus, nor the norepinephrine-induced release of arginine vasopressin from either amygdala or hypothalamus was affected by guanylate cyclase inhibitors, but all other arginine vasopressin releasers were blocked. Taken with previous reports that interferon-alpha will enhance hypothalamic corticotropin releasing hormone release, our results suggest that arginine vasopressin release enhanced by interferon-alpha may also contribute to the activation of the hypothalamic-pituitary axis, while the ability of transforming growth factor-beta 1 to diminish the arginine vasopressin released by acetylcholine could mediate some of this cytokine's central effects. The extension of these neurotransmitter-cytokine interactions to the amygdala may provide an additional basis for interactions between neuronal and immune systems.

Acetylcholine↗
PubMed1999

In vivo and in vitro characterisation of a nonpeptide vasopressin V(1A) and V(2) receptor antagonist (YM087) in the rat.

This paper reports the in vitro and in vivo characterisation of a nonpeptide, orally active, vasopressin V(1A) and V(2) receptor antagonist, YM087 (methyl-1,4,5,6-tetrahydroimidazo[4, 5-d][1]benzoazepine-6-carbonyl)-2-phenylbenzanilide monohydrochloride) in the rat. YM087 dose dependently displaced the vasopressin V(1A) receptor antagonist radioligand, 125I-labelled [d(CH(2))(5),sarcosine(7)]vasopressin at vasopressin V(1A) receptors in liver and kidney medulla membranes and caused a concentration dependent displacement of the vasopressin V(2) receptor antagonist radioligand [3H]desGly-NH(2)(9)[d(CH(2))(5), D-Ile(2), Ile(4)]vasopressin at vasopressin V(2) receptors in kidney medulla membranes. In vitro binding kinetic studies showed YM087 acted as a competitive antagonist at liver V(1A) and kidney V(1A) and V(2) vasopressin receptors. Oral administration of YM087 (0.1-3 mg/kg) dose dependently inhibited vasopressin binding to liver V(1A) and kidney V(1A) and V(2) vasopressin receptors over 24 h. Oral YM087 (1-3 mg/kg/day) for 7 days in normotensive rats caused a dose dependent aquaresis with no effect on systolic blood pressure. These results show that YM087 is an orally effective vasopressin V(1A) and V(2) receptor antagonist that may be useful in the treatment of conditions characterised by vasoconstriction and fluid retention such as congestive heart failure.

Administration, Oral↗
PubMed1998

Vasopressin combined with nitroglycerin increases endocardial perfusion during cardiopulmonary resuscitation in pigs.

Although vasopressin increases vital organ blood flow during cardiopulmonary resuscitation (CPR), endocardial perfusion remains suboptimal. This study was designed to assess the effects of vasopressin versus a combination of vasopressin and nitroglycerin on vital organ blood flow in a porcine model of CPR. After 4 min of cardiac arrest, and 3 min of closed-chest compressions, 14 animals were randomly treated with either 0.4 U/kg vasopressin (n = 7) or 0.4 U/kg vasopressin combined with 5 microg/kg nitroglycerin (n = 7). Coronary and cerebral perfusion pressure as well as left ventricular myocardial blood flow was comparable between groups throughout the experiment. Ninety seconds after drug administration, vasopressin combined with nitroglycerin resulted in comparison with vasopressin alone in significantly higher mean (+/- standard error of the mean) left ventricular endocardial blood flow (78+/-7 vs 51+/-5 ml x min(-1) x 100 g(-1); P < 0.05), and a significantly higher endocardial/epicardial perfusion ratio (0.93+/-0.09 vs 0.57+/-0.06; P < 0.05). Seven of seven animals in the vasopressin group, and four of seven animals in the vasopressin and nitroglycerin group (NS) were resuscitated successfully and survived the 2-h observation period. We conclude that, when compared with vasopressin therapy alone, combined vasopressin and nitroglycerin improved endocardial perfusion significantly immediately after drug administration during CPR.

Analysis of Variance↗
PubMed2001

Vasopressin- and oxytocin-induced activity in the central nervous system: electrophysiological studies using in-vitro systems.

During the last two decades, it has become apparent that vasopressin and oxytocin, in addition to playing a role as peptide hormones, also act as neurotransmitters/neuromodulators. A number of arguments support this notion: (i) vasopressin and oxytocin are synthesized not only in hypothalamo-neurohypophysial cells, but also in other hypothalamic and extrahypothalamic cell bodies, whose axon projects to the limbic system, the brainstem and the spinal cord. (ii) Vasopressin and oxytocin can be shed from central axons as are classical neurotransmitters. (iii) Specific binding sites, i.e. membrane receptors having high affinity for vasopressin and oxytocin are present in the central nervous system. (iv) Vasopressin and oxytocin can alter the firing rate of selected neuronal populations. (v) In-situ injection of vasopressin and oxytocin receptor agonists and antagonists can interfere with behavior or physiological regulations. Morphological studies and electrophysiological recordings have evidenced a close anatomical correlation between the presence of vasopressin and oxytocin receptors in the brain and the neuronal responsiveness to vasopressin or oxytocin. These compounds have been found to affect membrane excitability in neurons located in the limbic system, hypothalamus, circumventricular organs, brainstem, and spinal cord. Sharp electrode intracellular recordings and whole-cell recordings, done in brainstem motoneurons or in spinal cord neurons, have revealed that vasopressin and oxytocin can directly affect neuronal excitability by opening non-specific cationic channels or by closing K(+) channels. These neuropeptides can also influence synaptic transmission, by acting either postsynaptically or upon presynaptic target neurons or axon terminals. Whereas, in cultured neurons, vasopressin and oxytocin appear to mobilize intracellular Ca(++), in brainstem slices, the action of oxytocin is mediated by a second messenger that is distinct from the second messenger activated in peripheral target cells. In this review, we will summarize studies carried out at the cellular level, i.e. we will concentrate on in-vitro approaches. Vasopressin and oxytocin will be treated together. Though acting via distinct receptors in distinct brain areas, these two neuropeptides appear to exert similar effects upon neuronal excitability.

Animals↗
PubMed1988

Autoradiographic localization of vasopressin and oxytocin binding sites in rat kidney.

The presence of vasopressin receptors of the V1 (vascular) type and of oxytocin receptors in the rat kidney was investigated using an autoradiographical approach. Rat kidney sections were incubated with tritiated vasopressin ([3H]vasopressin, 1.5 nM) or oxytocin ([3H]oxytocin, 3 nM). The ligand selectivity of the [3H]vasopressin binding sites detected was deduced from competition experiments using one selective unlabeled ligand for V2 (antidiuretic) vasopressin receptors (1-deamino-[8-D-arginine]-vasopressin, dDAVP) and one selective unlabeled ligand for V1 receptors (des-glycineamide-[1-(beta-mercapto-beta,beta-cyclopentamethylene propionic acid]-arginine vasopressin, des(Gly(NH2)9d(CH2)5-AVP). Specific and dense [3H]vasopressin labeling was observable in the medullopapillary and cortical portions of the kidney. Specific [3H]vasopressin binding in the cortex was insensitive to the V1-selective ligand, des(Gly(NH2)9d(CH2)5-AVP, but was inhibited by dDAVP. Glomerular structures identified as such by microscopical observation of the kidney sections were specifically labeled with [3H]oxytocin and [125I]-SAR1-angiotensin II but not with [3H]vasopressin. It is concluded that V1 receptors which have been evidenced on mesangial cells in culture are not expressed in a detectable quantity on mesangial cells in situ. The specific [3H]oxytocin binding to glomeruli might reflect the presence on glomerular structures of oxytocin receptors involved in the effects of the hormone on renal hemodynamics, and possibly in some of the effects ascribed to vasopressin.

Animals↗
PubMed1986

Glucagon and vasopressin interactions on Ca2+ movements in isolated hepatocytes.

The effects of glucagon and vasopressin, singly or together, on cytosolic free Ca2+ concentration [( Ca2+]i) and on the 45Ca2+ efflux were studied in isolated rat liver cells. In the presence of 1 mM external Ca2+, glucagon and vasopressin added singly induced sustained increases in [Ca2+]i. The rate of the initial fast phase of the [Ca2+]i increase and the magnitude of the final plateau were dependent on the concentrations (50 pm-0.1 microM) of glucagon and vasopressin. Preincubating the cells with a low concentration of glucagon (0.1 nM) for 2 min markedly accelerated the fast phase and elevated the plateau of the [Ca2+]i increase caused by vasopressin. In the absence of external free Ca2+, glucagon and vasopressin transiently increased [Ca2+]i and stimulated the 45Ca2+ efflux from the cells, indicating mobilization of Ca2+ from internal store(s). Preincubating the cells with 0.1 nM-glucagon accelerated the rate of the fast phase of the [Ca2+]i rise caused by the subsequent addition of vasopressin. However, unlike what was observed in the presence of 1 mM-Ca2+, glucagon no longer enhanced the maximal [Ca2+]i response to vasopressin. In the absence of external free Ca2+, higher concentrations (1 nM-0.1 microM) of glucagon, which initiated larger increases in [Ca2+]i, drastically decreased the subsequent Ca2+ response to vasopressin (10 nM). At these concentrations, glucagon also decreased the vasopressin-stimulated 45Ca2+ efflux from the cells. It is suggested that, in the liver, glucagon accelerates the fast phase and elevates the plateau of the vasopressin-mediated [Ca2+]i increase respectively by releasing Ca2+ from the same internal store as that permeabilized by vasopressin, probably the endoplasmic reticulum, and potentiating the influx of extracellular Ca2+ caused by this hormone.

Animals↗
PubMed1996

Osmoregulation of plasma vasopressin in diabetes mellitus with sustained hyperglycemia.

We studied osmoregulation of plasma vasopressin in 5 patients with newly diagnosed diabetes mellitus. All patients showed typical symptoms of uncontrolled diabetes mellitus such as marked hyperglycemia, polyuria, and polydipsia, but did not have advanced diabetic complications. Vasopressin release was studied using 5% hypertonic saline infusion test twice: before treatment when the patient was hyperglycemic, and after treatment 1 to 2 months later when the patient was euglycemic. Plasma vasopressin was measured by a sensitive and specific radioimmunoassay. The mean basal plasma vasopressin value in the patients was significantly higher in the hyperglycemic compared with the euglycemic state (3.75 +/- 0.70 vs 1.18 +/- 0.46 pmol/l, respectively; P < 0.05). The relationship of plasma vasopressin with serum sodium, but not plasma osmolality, during hyperglycemia showed an apparent hypersecretion of vasopressin. In both cases, the sensitivity of the vasopressin response to osmotic stimuli was significantly decreased. During euglycemia, the sensitivity of vasopressin secretion to either sodium or osmolality was almost normal, although a slight rise in the osmostat was observed compared with normal subjects. Together, we found that the positive correlation of vasopressin with sodium or osmolality is maintained but significantly altered in patients with untreated diabetes mellitus. Especially noteworthy is the lowered threshold and decreased sensitivity of osmotically-induced vasopressin secretion during hyperglycemia, which may be caused by multiple factors such as diabetes-associated hypovolemia, osmogenic effects of glucose and other osmoles, depletion of the pool of vasopressin available for release, and the metabolic derangement of osmoreceptor/magnocellular neurons.

Adult↗
PubMed1996

Identification of metabolic pathways of brain angiotensin II and III using specific aminopeptidase inhibitors: predominant role of angiotensin III in the control of vasopressin release.

Angiotensin (Ang) II and Ang III are two peptide effectors of the brain renin-angiotensin system that participate in the control of blood pressure and increase water consumption and vasopressin release. In an attempt to delineate the respective roles of these peptides in the regulation of vasopressin secretion, their metabolic pathways and their effects on vasopressin release were identified in vivo. For this purpose, we used recently developed selective inhibitors of aminopeptidase A (APA) and aminopeptidase N (APN), two enzymes that are believed to be responsible for the N-terminal cleavage of Ang II and Ang III, respectively. Mice received [3H]Ang II intracerebroventricularly (i.c.v.) in the presence or absence of the APN inhibitor, EC33 (3-amino-4-thio-butyl sulfonate) of the APN inhibitor, EC27 (2-amino-pentan-1,5-dithiol). [3H]Ang II and [3H]Ang III levels were evaluated from hypothalamus homogenates by HPLC. EC33 increased the half-life of [3H]Ang II 2.6-fold and completely blocked the formation of [3H]Ang III, whereas EC27 increased the half-life of [3H]Ang III 2.3-fold. In addition, the effects of EC33 and EC27 on Ang-induced vasopressin release were studied in mice. Ang II was injected i.c.v. in the presence or absence of EC33, and plasma vasopressin levels were estimated by RIA. While vasopressin levels were increased 2-fold by Ang II (5 ng), EC33 inhibited Ang II-induced vasopressin release in a dose-dependent manner. In contrast, EC27 injected alone increased in a dose-dependent manner vasopressin levels. The EC27-induced vasopressin release was completely blocked by the coadministration of the Ang receptor antagonist (Sar1-Ala8) Ang II. These results demonstrate for the first time that (i) APA and APN are involved in vivo in the metabolism of brain Ang II and Ang III, respectively, and that (ii) the action of Ang II on vasopressin release depends upon the prior conversion of Ang II to Ang III. This shows that Ang III behaves as one of the main effector peptides of the brain renin-angiotensin system in the control of vasopressin release.

Amino Acid Sequence↗
PubMed1996

Effects of graded doses of vasopressin on median fibrillation frequency in a porcine model of cardiopulmonary resuscitation: results of a prospective, randomized, controlled trial.

OBJECTIVE: To assess the effects of graded doses of vasopressin vs. saline on median fibrillation frequency and defibrillation success in a porcine model of cardiopulmonary resuscitation. DESIGN: Prospective, randomized, controlled trial. SETTING: Animal laboratory in a university medical center. SUBJECTS: Twenty-eight domestic pigs (body weight between 26 and 31 kg), aged 12 to 14 wks. INTERVENTIONS AND MAIN RESULTS: After 4 mins of ventricular fibrillation and 3 mins of closed-chest cardiopulmonary resuscitation, the animals were allocated to receive either 0.2 U/kg of vasopressin (n = 7), 0.4 U/kg of vasopressin (n = 7), 0.8 U/kg of vasopressin (n = 7), or 10 mL of saline (n = 7, control group). Using radiolabeled microspheres, myocardial blood flow rates during cardiopulmonary resuscitation-before drug administration and 90 secs and 5 mins after drug administration-were as follows in the four groups (mean +/- SEM): 18.8 +/- 0.9, 17.2 +/- 1.1, and 14.6 +/- 1.4 mL/min/100 g in the control group; 17.8 +/- 2.2, 49.6 +/- 6.3 (p < .01 vs. control group), and 29.4 +/- 3.1 mL/min/100 g (p < .05 vs. control group) in the group receiving 0.2 U/kg of vasopressin; 17.1 +/- 1.0, 52.4 +/- 7.5 (p < .01 vs. control group), and 52.2 +/- 5.8 mL/min/100 g (p < .001 vs. control group) in the group receiving 0.4 U/kg of vasopressin; and 18.1 +/- 1.6, 94.9 +/- 9.2 (p < .001 vs. control group), and 57.2 +/- 6.3 mL/min/100 g (p < .001 vs. control group) in the group receiving 0.8 U/kg of vasopressin. Using spectral analysis, median frequencies of ventricular fibrillation-before drug administration and 90 secs and 5 mins after drug administration-were as follows in the four groups: 9.6 +/- 0.4, 8.5 +/- 0.8, and 7.2 +/- 1.0 Hz in the control group; 9.7 +/- 0.5, 12.9 +/- 0.8 (p < .01 vs. control group), and 12.7 +/- 0.8 Hz (p < .001 vs. control group) in the group receiving 0.2 U/kg of vasopressin; 10.3 +/- 0.2, 12.7 +/- 0.9 (p < .01 vs. control group), and 12.8 +/- 0.7 Hz (p < .001 vs. control group) in the group receiving 0.4 U/kg of vasopressin; and 10.0 +/- 0.9, 14.1 +/- 0.9 (p < .001 vs. control group), and 12.5 +/- 0.9 Hz (p < .001 vs. control group) in the group receiving 0.8 U/kg of vasopressin at the same points in time. Median frequency before the first defibrillation attempt was 12.3 +/- 0.4 Hz in the resuscitated animals (n = 19) and 8.2 +/- 1.2 Hz in the nonresuscitated animals (n = 9) (p < .001). CONCLUSIONS: This study contributes to the characterization of the effect of increasing global myocardial blood flow on median fibrillation frequency after administration of graded doses of vasopressin in a porcine model of ventricular fibrillation. Interventions such as vasopressor treatment that increase fibrillation frequency improve the chance of successful defibrillation.

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