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PubMed1996

Metabolism of vasopressin, oxytocin and their analogues [Mpa1, D-Arg8]-vasopressin (dDAVP) and [Mpa1, D-Tyr(Et)2, Thr4, Orn8]-oxytocin (antocin) in human kidney and liver homogenates.

Information regarding the metabolic fate of the neurohypophyseal hormones arginine-vasopressin (AVP), oxytocin (OT) and their analogues in man is practically non-existent. The aim of the present study was to investigate the stability of oxytocin, vasopressin and their analogues dDAVP and [Mpa1-D-Tyr2(Et), Thr4, Orn8]-oxytocin (antocin) in human renal microvilli brush border membranes and in human liver membranes. After incubation the extent of degradation of the peptides was determined by reversed phase high-performance liquid chromatography (HPLC). The degradation of both AVP and OT was rapid in the presence of glutathione and human renal microvilli membranes. AVP, as well as dDAVP, was stable when incubated with microvilli membranes without glutathione, while OT was metabolized. The metabolization of the oxytocin analogue, antocin, also varied with the presence of glutathione. While in the absence of glutathione a more lipophilic peak eluted, a more hydrophilic peak was observed with glutathione on HPLC. The lipophilic peak was found to coelute with the truncated analogue [Mpa1, D-Tyr2 (Et), Thr4, desOrn8, Gly9]-oxytocin. No degradation occurred when the peptides were incubated with liver membranes. However, when using crude, unpurified liver homogenate degradation occurred for all peptides except antocin. The degradation of AVP in the human unpurified liver homogenate was as rapid as in the renal microvilli membranes. Similarly, OT was more rapidly degraded in human kidney microvilli membranes in the presence of glutathione than in the human crude liver homogenate, when using equal amounts of protein in the incubations. Thus, the present investigation indicates the existence of two possible metabolic pathways, in kidney microvilli, one for OT, which did not require the presence of reduced glutathione, and one for AVP, which required the presence of reduced glutathione. Liver degradation, on the other hand, requires the hepatocytes.

Arginine Vasopressin↗
PubMed2002

Effect of conivaptan, a combined vasopressin V(1a) and V(2) receptor antagonist, on vasopressin-induced cardiac and haemodynamic changes in anaesthetised dogs.

The neurohormonal factor arginine vasopressin (AVP) produces potent systemic vasoconstriction as well as water retention in the kidneys via the V(1a) and V(2) receptors, respectively. Therefore, AVP may be considered as an aggravating factor of cardiac failure. In the present study, the effects of intravenous (i.v.) infusion of AVP on cardiovascular parameters and the effect of conivaptan (YM087, 4'-(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzoazepine-6-carbonyl)-2-phenylbenzanilide monohydrochloride), a vasopressin V(1a)/V(2) receptor antagonist, on AVP-induced cardiac and haemodynamic changes were investigated in pentobarbitone-anaesthetised dogs. The i.v. infusion of AVP (0.12-4mUkg(-1)min(-1)) dose-dependently produced decreases in the cardiac contractility indicator LV dP/dt(max) and cardiac output (CO) and increases in left ventricular end-diastolic pressure (LVEDP) and total peripheral resistance (TPR). These changes accurately mimic the cardiovascular symptoms of congestive heart failure. The i.v. bolus injection of conivaptan (0.1mgkg(-1)) rapidly attenuated the AVP (4mUkg(-1)min(-1))-induced decrease in CO and reversed the AVP-induced elevation in both LVEDP and TPR. In conclusion, i.v. infusion of AVP produced cardiac dysfunction and vasoconstriction in pentobarbitone-anaesthetised dogs. Conivaptan demonstrated the ability to dramatically improve the impaired cardiovascular parameters induced by AVP. The results suggest the potential usefulness of conivaptan in treating congestive heart failure.

Anesthesia↗
PubMed1983

Potent antagonists of the antidiuretic responses to arginine-vasopressin based on modifications of [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid),2-D- phenylalanine,4-valine]arginine-vasopressin at position 4.

As part of a program in which we are attempting (a) to delineate the structural features at positions 1-9 in our previously reported antidiuretic antagonists required for antidiuretic antagonism and (b) to obtain analogues with enhanced antiantidiuretic potency and/or selectivity, we have synthesized 14 new analogues of the antidiuretic antagonist [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid),2-D-phenylalanine,4-valine]arginine-vasopressin [d-(CH2)5-D-Phe2VAVP), in which the valine residue at position 4 was replaced by the following L-amino acids and glycine: Ile, Abu, Thr, Ala, Gln, Lys, Cha, Nle, Nva, Phe, Leu, Gly, Tyr, and Pro. These analogues are 1, d-(CH2)5-D-Phe2,Ile4AVP; 2, d(CH2)5-D-Phe2,Abu4AVP; 3, d(CH2)5-D-Phe2,Thr4AVP; 4, d(CH2)5-D-Phe2,Ala4AVP;5, d(CH2)5-D-Phe2AVP; 6, d(CH2)5-D-Phe2,Lys4AVP; 7, d(CH2)5-D-Phe2,Cha4AVP; 8, d(CH2)5-D-Phe2,Nle4AVP; 9, d(CH2)5-D-Phe2,Nva4AVP; 10, d(CH2)5-D-Phe2,Phe4AVP; 11, d(CH2)5-D-Phe2,Leu4AVP; 12, d(CH2)5-D-Phe2,Gly4AVP; 13, d(CH2)5-D-Phe2,Tyr4AVP; 14, d(CH2)5-D-Phe2,Pro4AVP. The protected intermediates required for the synthesis of all of these peptides were prepared by the solid-phase method and cleaved from the resin by ammonolysis. Following deblocking with Na in NH3 and oxidizing with K3[Fe(CN)6], each peptide was purified on Sephadex G-15 in a two-step procedure using 50% HOAc and 0.2 M HOAc as eluants. Analogues 1-14 were tested for agonistic and antagonistic activities by antidiuretic, vasopressor, and oxytocic assays in rats. Analogues 1, 2, and 4-6 exhibit no detectable antidiuretic agonistic activity. All analogues, with the exception of the Pro4-containing analogue, are antidiuretic antagonists. Their antiantidiuretic pA2 values are as follows: 1, 8.24 +/- 0.08; 2, 7.96 +/- 0.07; 3, 7.62 +/- 0.09; 4, 7.52 +/- 0.03; 5, 7.21 +/- 0.07; 6, 7.22 +/- 0.12; 7, 7.19 +/- 0.08; 8, 7.12 +/- 0.09; 9, 6.99 +/- 0.06; 10, 6.07 +/- 0.11; 11, 6.07 +/- 0.11; 12, 5.85 +/- 0.05; 13, approximately 5.57; 14, a weak agonist (0.004 U/mg). Analogues 1-14 also antagonize the vascular responses to arginine-vasopressin (AVP) and the in vitro oxytocic responses to oxytocin. Analogues 1, 2, 3, and 5 have also been shown to antagonize the in vivo oxytocic responses to oxytocin. Five of these analogues (1, 2, 3, 6, and 7) exhibit enhanced antiantidiuretic/antivasopressor selectivity. d(CH2)5-D-Phe2,Lys4AVP and other position-4 analogues with side-chain functional groups may be useful covalent ligands with which to probe the structural characteristics of AVP renal and vascular receptors. With an antiantidiuretic "effective dose" of 0.46 +/- 0.07 nmol/kg and a pA2 value of 8.24 +/- 0.08, d(CH2)5-D-Phe2,Ile4AVP (1) appears to be the most potent antidiuretic antagonist reported to date.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2005

Selectivity of d[Cha4]AVP and SSR149415 at human vasopressin and oxytocin receptors: evidence that SSR149415 is a mixed vasopressin V1b/oxytocin receptor antagonist.

1 A possible role of arginine vasopressin (AVP) V(1b) receptor subtype in stress-related disorders has been recently highlighted by the discovery of the agonist [1-deamino-4-cyclohexylalanine] AVP (d[Cha(4)]AVP) and the antagonist SSR149415. Both compounds have been proposed to target specifically V(1b) receptors, since the reported affinities for the related V(1a), V(2) and oxytocin receptors are in the micromolar or submicromolar range. In the present study, we further investigated the binding affinities of d[Cha(4)]AVP and SSR149415 at recombinant human vasopressin V(1b) (hV(1b)) and oxytocin (hOT) receptors expressed in Chinese hamster ovary (CHO) cells and functional properties of both compounds at hV(1b), hV(1a), hV(2) and hOT receptors. 2 d[Cha(4)]AVP bound to hV(1b) receptors and hOT receptors with pK(i) values of 9.68+/-0.06 and 7.68+/-0.09, respectively. SSR149415 showed pK(i) values of 9.34+/-0.06 at hV(1b) and 8.82+/-0.16 at hOT receptors. 3 d[Cha(4)]AVP stimulated [Ca(2+)](i) increase in hV(1b)-CHO cells with a pEC(50) value of 10.05+/-0.15. It showed pEC(50) values of 6.53+/-0.17 and 5.92+/-0.02 at hV(1a) and hV(2) receptors, respectively, and behaved as a weak antagonist at hOT receptors (pK(B)=6.31+/-0.12). SSR149415 inhibited the agonist-induced [Ca(2+)](i) increase with pK(B) values of 9.19+/-0.07 in hV(1b)-CHO and 8.72+/-0.15 in hOT-CHO cells. A functional pK(i) value of 7.23+/-0.10 was found for SSR1494151 at hV(1a) receptors, whereas it did not inhibit 20 nM AVP response at hV(2) receptors up to 3 microM. 4 Data obtained confirmed the high potency and selectivity of d[Cha(4)]AVP at hV(1b) receptors, but revealed that SSR149415, in addition to the high potency at hV(1b) receptors, displays a significant antagonism at hOT receptors.

Animals↗
PubMed1975

Solid phase synthesis and some pharmacological properties of 8-D-homolysine-vasopressin and 1-deamino-8-D-homolysine-vasopressin.

8-DL-Homolysine-vasopressin and its 1-deamino derivative were synthesized by the solid phase method. The desired D-homolysine analogues were obtained by digestion of the mixtures with trypsin and isolation of the peptide components by ion-exchange chromatography. In agreement with earlier observations on vasopressins containing alpha, omega-diamino acids of D configuration the new analogues show very low pressor activities. However, the antidiuretic effects are surprisingly high, thus reversing the known activity trend and making the D-homolysine analogues highly selective antidiuretic agents.

Animals↗
PubMed1991

Effects of NG-nitro-L-arginine methyl ester or indomethacin on differential regional and cardiac haemodynamic actions of arginine vasopressin and lysine vasopressin in conscious rats.

1. Measurements of changes in renal, mesenteric and hindquarters haemodynamics or cardiac haemodynamics in response to i.v. bolus doses of arginine vasopressin (AVP) or lysine vasopressin (LVP, 0.7 and 7.0 pmol) were made in conscious, chronically-instrumented Long Evans rats. 2. In some experiments AVP and LVP were administered during an infusion of NG-nitro-L-arginine methyl ester (L-NAME; 1.0 or 0.3 mg kg-1 h-1) to determine whether or not inhibition of nitric oxide production influenced the cardiovascular effects of the peptides. In other experiments, indomethacin (bolus dose of 5 mg kg-1 followed by infusion at 5 mg kg-1 h-1) was given to determine the possible involvement of cyclo-oxygenase products in the responses to AVP and LVP. 3. Under control conditions, the lower dose of LVP had significantly greater effects than AVP on heart rate, mean arterial blood pressure, renal, mesenteric and hindquarters conductances, total peripheral conductance, cardiac index, peak aortic flow and +dF/dtmax. The higher dose of LVP had significantly greater effects than AVP on all variables (i.e. including stroke index and central venous pressure). 4. In the presence of L-NAME (1 mg kg-1 h-1) there was a sustained increase in mean arterial blood pressure (+23 +/- 3 mmHg) and reductions in mesenteric (-38 +/- 4%) and hindquarters (-30 +/- 6%) vascular conductances. Under these conditions the difference in the pressor effects of AVP and LVP was abolished, but their differential effects on regional and cardiac haemodynamics persisted. This dose of L-NAME did not change cardiac baroreflex sensitivity. 5. During infusion of L-NAME at a lower rate (0.3mgkg-th-1), baseline cardiovascular status was unchanged and regional haemodynamic effects of AVP and LVP were enhanced, but the differences in the regional vasoconstrictor responses to the two peptides persisted. 6. Indomethacin (5 mg kg-1 bolus, then 5 mg kg- 'h-1 infusion) augmented the renal vasoconstrictor responses to AVP and LVP, but abolished the difference in the hindquarters vasoconstrictor responses to the two peptides. However, the differences in the pressor and the renal and mesenteric vasoconstrictor effects of AVP and LVP still occurred in the presence of indomethacin. 7. The results indicate that AVP normally has lesser cardiovascular effects than LVP but this difference does not seem to be due to more effective stimulation of nitric oxide-mediated or cyclo-oxygenase-dependent vasodilator mechanisms by AVP than LVP.

Animals↗
PubMed1978

Actions of a new vasopressin analogue (1-deamino-6-carba-[8-arginine]-vasopressin) on regional blood flow in pregnant guinea pigs.

Regional blood flow responses to 1-deamino-6-carba-(8-arginine)-vasopressin (dCAVP) were investigated in pregnant guinea pigs by the radioactive microsphere technique. Intravenous injection of 0.1 microgram/kg body weight caused a moderate rise in mean arterial blood pressure from 6.8 to 7.9 kPa, a significant reduction in tissue perfusion of the stomach, mammary gland, urinary bladder and vagina, and a significant increase in renal and cerebral blood flow. In a small number of animals given 1.0 microgram/kg of dCAVP, which evoked a strong pressor response, it was also possible to demonstrate a reduction in cutaneous and pancreatic blood flow and an augmentation of adrenal blood flow. Uterine and maternal placental blood flow did not alter significantly following administration of this vasopressin analogue.

Animals↗
PubMed1981

Prolonged inhibition of pressor response to vasopressin by a potent specific antagonist, [1-(beta-mercapto-beta, beta-cyclopentamethylenepropionic acid) 2-(O-methyl)tyrosine]arginine-vasopressin.

The specificity, the potency, and the duration of action of [1-(beta-mercapto-beta, beta-cyclopentamethylenepropionic acid) 2-(O-methyl)tyrosine]arginine-vasopressin[d(CH2)5Tyr(Me)AVP] to antagonize pressor responses to arginine vasopressin (AVP) was examined in pentobarbital-anaesthetized rats. Injection of the compound (4 micrograms.kg-1 i.v.) prevented pressor responses to i.v. infusions of supramaximal doses of AVP, but not to i.v. infusions of another peptide, angiotensin II (Ag II). The antagonism of AVP persisted for at least 3 h. Since i.v. injection of the compound in the absence of exogenous administration of AVP did not cause any change in the arterial pressure of rats, it appears that the compound is devoid of agonistic pressor activity. The results show that d(CH2)5Tyr(Me)AVP is a potent and a specific antagonist of pressor responses to AVP.

Animals↗
PubMed1989

Renal microvascular effects of vasopressin and vasopressin antagonists.

The effects of vasopressin (AVP) and vasopressin antagonists on lumen diameters of cortical afferent and efferent arterioles isolated from rabbit kidneys were examined. Over a concentration range of 10(-14) to 10(-7) M, AVP had no effect on lumen diameters of afferent arterioles, although the arterioles were responsive to norepinephrine. Similarly, addition of 10(-8) M AVP to the lumen of afferent arterioles or to the bath of arterioles pretreated with indomethacin had no effect. In contrast, AVP caused a concentration-dependent reduction of lumen diameters of efferent arterioles. AVP was approximately 100-fold more potent than norepinephrine in producing contraction of efferent arterioles. The V1-selective antagonist, [d(CH2)5Tyr(Me)]AVP, and the V1/V2-antagonist, d(CH2)5D-Tyr(Et) desGlyVAVP, inhibited the vasoconstriction produced by AVP in a concentration-dependent but noncompetitive manner. The V2-selective antagonist, [d(CH2)5D-Ile]VAVP, had no significant effect on AVP-induced vasoconstriction. We conclude that, under the in vitro conditions used, AVP selectively contracts efferent arterioles. The results provide direct evidence for a postglomerular vascular effect of AVP in the renal cortex. This activity, together with its previously described effects on the glomerulus, suggests that AVP may produce changes in glomerular function and/or peritubular forces that are involved in tubular reabsorption.

Animals↗
PubMed1989

Central vasopressin raises arterial pressure by sympathetic activation and vasopressin release.

Although central administration of arginine vasopressin (AVP) has been reported to increase arterial pressure mediated by activation of the sympathetic system, we found that peripheral blockade of sympathetic transmission did not attenuate this pressor response. To elucidate the mechanism, rats were pretreated with either phentolamine (3 mg/kg), chlorisondamine (2.5 mg/kg), a vasopressin V1 receptor antagonist d(CH2)5Tyr(Me)AVP (AVP-X) (10 micrograms/kg), or the combinations of phentolamine and AVP-X or chlorisondamine and AVP-X. The pressor response to intracerebroventricular injection of AVP in unrestrained conscious rats was reduced but not significantly altered by intravenous injection of phentolamine or AVP-X; however, combined treatment with these agents abolished the response. To determine that the amount of central AVP leaked to the periphery did not contribute to the pressor effect, tritiated AVP and AVP (100 ng total) were injected intracerebroventricularly. Blood samples collected at 0, 3, and 30 minutes after injection showed that radioactivity in plasma was primarily metabolites and that the amount of intact AVP estimated to leak from the brain was too low to produce a pressor effect. Comparative regional hemodynamic studies between intracerebroventricular and intravenous injection of AVP performed in conscious rats instrumented with Doppler flow probes demonstrated a qualitatively similar pattern of increased resistance in the renal, mesenteric, and hindquarters beds. These data suggest that central pressor action of AVP is mediated by both activation of the sympathetic system and release of AVP.

Animals↗
PubMed1997

Effects of SR 49059, a new orally active and specific vasopressin V1 receptor antagonist, on vasopressin-induced vasoconstriction in humans.

We have evaluated the efficacy of SR 49059, a new orally active and specific vasopressin V1 receptor antagonist (arginine-vasopressin [AVP]), in the blockade of the vascular effects of exogenous AVP in healthy subjects. In preliminary experiments, two procedures to measure the V1 vascular effects of AVP were assessed. First, the AVP-induced changes in skin blood flow were investigated by the injection of increasing doses of AVP intradermally, with or without a previous local vasodilation with calcitonin gene-related peptide (CGRP). In a second protocol, AVP was infused intra-arterially, and the changes in radial artery diameter and blood flow were measured. The intradermal injection of AVP caused significant decreases in skin blood flow, and the use of CGRP increased the sensitivity of the method by a factor of 10(2) to 10(3). AVP infused intra-arterially caused dose-dependent decreases in the radial artery diameter and blood flow. In the main study, the potency and efficacy of SR 49059 to block the AVP-induced changes in skin blood flow were assessed in 12 healthy men with a double-blind, triple crossover study design. The subjects were randomized to receive a placebo orally and 30 mg and 300 mg of the antagonist at a 1-week interval. The subjects were then further randomized to evaluate the efficacy of the same doses of the antagonist to block the vasoconstriction of the radial artery induced by an intra-arterial infusion of AVP. SR 49059 inhibits, dose-dependently and significantly, the AVP-induced changes in skin blood flow, with a peak effect occurring between 2 and 6 hours after injection. In addition, the 300-mg dose of SR 49059 completely blocked the vasoconstriction of the radial artery induced by AVP. In conclusion, skin blood-flow measurement, after intradermal injection of AVP on a skin area vasodilated with CGRP, is an effective method to investigate the V1 vascular effect of AVP in humans. SR 49059 is a potent and specific antagonist of V1 receptors, which blocks the AVP-induced vasoconstriction.

Administration, Oral↗
PubMed1985

Inhibition of vasopressin-stimulated water flow in toad bladder by phorbol myristate acetate, dioctanoylglycerol, and RHC-80267. Evidence for modulation of action of vasopressin by protein kinase C.

The action of vasopressin (AVP) in transporting epithelia is mediated by cyclic AMP(cAMP), whereas its effects in hepatocytes are mediated by calcium and phosphoinositides. Based on our recent observation that AVP stimulates phosphoinositide turnover in toad bladder, we examined the role of calcium-phospholipid-dependent kinase (protein kinase C) as a modulator of AVP's hydroosmotic effect. Phorbol myristate acetate (PMA), which can substitute for diglyceride as an activator of protein kinase C, the diglyceride dioctanoylglycerol, and RHC-80267, a glyceride lipase inhibitor that should increase diglyceride levels, inhibited AVP-stimulated water flow, but not water flow stimulated by cAMP, suggesting inhibition of cyclic AMP production. Both the dioctanoylglycerol and RHC-80267, but not PMA, also decreased water flow in response to 8-bromo cAMP indicating a potential inhibition at post-cAMP events as well. PMA increased prostaglandin synthesis; however, inhibition of water flow persisted even when prostaglandin synthesis was completely blocked by incubation with naproxen. Furthermore, water flow was not inhibited by incubation with the inactive diglyceride substitute phorbol didecanoate, supporting the specificity of the PMA inhibition. Consistent with the site of action at adenylate cyclase suggested by the transport experiments, PMA and RHC-80237 decreased both cell cAMP content and the cyclic AMP-dependent kinase ratio (-cAMP/+cAMP), an index of intracellular cyclic AMP effect. Assay for protein kinase C activity in toad bladder epithelial cell supernatant demonstrated that the toad bladder indeed contains a kinase stimulable by phospholipid, calcium, and PMA. As an apparently independent effect, we found that addition of PMA, but not dioctanoylglycerol or RHC-80267, to the mucosal bath increased both water permeability and the frequency of granular cell luminal membrane aggregates in the absence of vasopressin, consistent with stimulation of fusion events at the luminal membrane. Our data suggest that protein kinase C can modulate AVP-stimulated water flow in toad bladder by inhibiting cAMP generation, and perhaps post-cAMP steps as well, and support the hypothesis that AVP-stimulated turnover of membrane phosphoinositides antagonize the effects of AVP via changes in diglyceride, calcium, and protein kinase C.

Animals↗
PubMed1987

Vasopressin-containing and vasopressin-deficient subpopulations of corticotropin-releasing factor axons are differentially affected by adrenalectomy.

CRF-containing parvocellular axons in the external zone of the rat median eminence were classified as vasopressin-containing (CRF+/AVP+) and vasopressin-deficient (CRF+/AVP-) subpopulations based on post-embedding electron microscopic immunocytochemical staining of serial ultrathin sections for CRF, AVP and the other peptides derived from the AVP precursor: AVP-associated neurophysin (NP-AVP) and the C-terminal glycopeptide (GP). In normal animals, the CRF+/AVP+ and CRF+/AVP- subpopulations were approximately equal in terms of detectable axonal swellings. Three to 14 days after adrenalectomy (ADX), the CRF+/AVP+ and CRF+/AVP- subpopulations represented about 95% and 5%, respectively, of total CRF+ swellings. This change was due to a 90% decrease in the absolute number of detectable CRF+/AVP- swellings after ADX, whereas the absolute number of detectable CRF+/AVP+ swellings rose by less than 20%. These changes were completely blocked by administering the glucocorticoid agonist dexamethasone throughout the period after ADX. The results suggest that the CRF+/AVP+ and CRF+/AVP- subpopulations of neurosecretory axons in the external zone of the median eminence respond differently to ADX, indicating that they are independently regulated by glucocorticoids.

Adrenalectomy↗
PubMed1994

Alprazolam attenuates vasopressin-stimulated adrenocorticotropin and cortisol release: evidence for synergy between vasopressin and corticotropin-releasing hormone in humans.

Alprazolam (APZ), a triazolobenzodiazepine with unique clinical utility, has potent inhibitory effects on the human hypothalamic-pituitary-adrenal axis. Because APZ inhibits CRH secretion from isolated rat hypothalami and inhibits the probable CRH-mediated effect of naloxone on ACTH release, it is likely APZ acts as an inhibitor of hypothalamic CRH release in humans. The two principal physiological ACTH secretagogues are CRH and arginine vasopressin (AVP). We studied the ACTH and cortisol responses to an ACTH-releasing dose of AVP with and without preadministration of APZ in humans. Our hypothesis was that acute CRH deprivation by APZ would attenuate the ACTH response to vasopressin, as CRH and AVP act synergistically to control ACTH release. This synergy may depend on activation of subpopulations of corticotropes, some of which require both CRH and AVP together to elicit an ACTH response and/or intracellular "cross-talk" between second messenger pathways stimulated by the secretagogues. APZ (2 mg, orally) was given to eight healthy volunteers 90 min before AVP (0.0143 IU/kg BW, iv) in a randomized, double blind, placebo-controlled design during afternoon studies. ACTH and cortisol levels were measured at frequent intervals from 60 min before to 120 min after AVP injection. APZ reduced the mean integrated ACTH and cortisol responses to AVP by 67% and 70% respectively [ACTH, 161.6 +/- 59.7 vs. 53.0 +/- 20.9 pmol/min.L (P = 0.022); cortisol, 9314 +/- 3310 vs. 2763 +/- 1472 nmol/min.L (P = 0.020, AVP vs. APZ/AVP, respectively)]. APZ reduced the mean peak ACTH and cortisol responses to AVP by 57% (P = 0.023) and 40% (P = 0.0012), respectively. AVP levels were not significantly different in those who received APZ or placebo. This study provides further evidence of the potent inhibitory effects of APZ on ACTH and cortisol release in humans and is the first to find that APZ inhibits AVP-stimulated ACTH and cortisol release. This study also suggests that CRH/AVP synergy is an important physiological mechanism for ACTH release in humans, as indicated by the blunted ACTH response to AVP after APZ-mediated acute CRH deprivation. Inhibition of the pituitary-adrenal axis by APZ may explain its unique efficacy in psychiatric disorders thought to be associated with dysregulation of hypothalamic CRH release.

Adrenocorticotropic Hormone↗
PubMedDate not supplied

Vasopressin and hepatic artery. Effect of selective celiac infusion of vasopressin on the hepatic artery flow.

Electromagnetic flow measurement study was performed in 20 anesthetized dogs to evaluate the effect of selective celiac infusion of vasopressin on the hepatic arterial vasculature. Teh hepatic arterial flow showed a biphasic response with an initial decrease followed by a substantial increase in spite of a continued infusion. The left gastric, splenic, and superior mesentric arteries showed a monophasic response with persistent decrease of flow during the whole infusion. The biphasic response of the hepatic arterial flow is thought to be due to autoregulatory dilative action of the liver to a decrease of the portal flow. The results and previous clinical experience suggest that the selective infusions of vasopressin into arteries supplying the liver can be used for short-term vasoconstrictive therapy of acute gastrointestinal bleeding in patients without liver damage. Further experience is necessary to evaluate the safety of prolonged hepatic infusions in patients with liver damage.

Animals↗
PubMedDate not supplied

[The slowing of the extinction of a conditioned reaction and the antiamnesic action of arginine vasopressin and des-glycine-(8-arginine) vasopressin].

In the experiments on mice there were analysed the effects of arginine-vasopressin (AVP) and its analogue des-glycine-arginine-vasopressin (DG-AVP) on the extinction of the conditioned reaction of passive avoidance and the reproduction of memory trace in amnesia caused by detaining the animal in the dangerous section of the unit after electrocutaneous stimulation. An increase of resistance of the conditioned reaction to a sharp extinction at systemic administration of AVP and DG-AVP was shown.

Amnesia↗
PubMed1985

Relationship between vasopressin and the renin-angiotensin-aldosterone system in essential hypertension: effect of converting enzyme inhibitor on plasma vasopressin.

The effect of the chronic administration of captopril on plasma levels of vasopressin (PVP) were studied in 14 patients with moderate essential hypertension and 10 normal volunteers. All patients were studied after 10 days without drugs and under a constant diet (120 mmol sodium and 80 mmol potassium/day). Plasma levels of renin activity (PRA), aldosterone (PA) and PVP were assayed before and after captopril treatment (50-100 mg/day for 1 month). In addition to the well-known effect of captopril treatment on PRA and PA, a statistically significant reduction of PVP was observed. This finding suggests that the renin-angiotensin-aldosterone system influences vasopressin release, and its inhibitors may contribute to the absence of water retention during captopril treatment compared with the effect of other vasodilatory drugs.

Adult↗
PubMed1987

Arginine-vasopressin and lysine-vasopressin have different effects on spontaneous behaviour of rats.

Two groups of each 8 adult male hooded rats of the Long-Evans strain received single subcutaneous injections of 1 microgram/kg arginine-vasopressin (AVP) or 1 microgram/kg lysine-vasopressin (LVP) 15 min before investigation in an open field (OF) and 30 min before investigation of locomotion in a wheel (W). The behavioural parameters were statistically compared with two control groups. AVP significantly increased infrared beam crossings in the OF, wheel-running and the mobility of the rats in both tests. LVP had a strong just opposite effect. LVP facilitated habituation and AVP weakened it. AVP facilitated rearing, whereas LVP suppressed it. The duration of immobility was strongly enhanced after LVP in both tests (380% in the OF and 920% in the W) but AVP had no prolonging effect. The latency of the first immobility phase in the OF was increased to 250% after AVP and decreased to 45% after LVP. Grooming was not influenced by AVP, whereas LVP strongly reduced the grooming duration and prolonged the grooming latency in the OF. The contrary effects of AVP and LVP are highly significant. They may be summarized as activating effect on motor behaviour and exploration by AVP and inhibitory action of LVP.

Animals↗