Effect of vasopressin on open field and activity behavior of the vasopressin-deficient (Brattleboro) rat

The effect of 1 and 5 micrograms AVP injections on open field and photoactivity chamber behavior of D.I. and normal Long-Evans animals was studied. Administration of 5 micrograms AVP (SC) resulted in a statistically significant depression of both open field and photochamber activity in the D.I. rat, but had a less pronounced effect on normal animals. However, 1 microgram AVP resulted in only minor alterations of activity in both D.I. and normal animals. In terms of learned behavior, D.I. and normal animals displayed similar within-session habituation when comparisons were made following the same treatment conditions. Thus, this study supports the hypothesis that vasopressin may influence memory tasks by modulation of related states of emotionality, motivation, and/or attention rather than by direct involvement in the retrieval and/or consolidation of information.     

Novel,potent, selective and brain penetrant vasopressin 1b receptor antagonists

Herein we report the discovery of a novel oxindole-based series of vasopressin 1b (V1b) receptor antagonists. Introducing a substituted piperazine moiety and optimizing the southern and the northern aromatic rings resulted in potent, selective and brain penetrant V1b receptor antagonists. Compound 9c was found to be efficacious in a rat model of anti-depressant activity (3?mg/kg, ip). Interestingly, both moderate terminal half-life and moderate bioavailability could be achieved despite sub-optimal microsomal stability.     

Effects of vasopressin on the habituation of the orienting reaction in men

Effects of arginine-vasopressin (AVP) on the habituation of the orienting reaction and response to stimulus mismatch were investigated in a between-group design with 40 healthy male volunteers using skin conductance and heart rate responses as dependent measures. Twenty-one 1000 Hz tones of 90 dB(A) intensity and 2 s duration were presented with alternating intervals of 20 and 140 s. Stimulus mismatch responses were analyzed to the tones after the long intervals and to a change of the interval duration. The expected prevention of habituation as an indicator of a general stimulus-related increase of phasic arousal under AVP could not be confirmed. There were no differences between the AVP and the placebo group in the skin conductance and heart rate responses. The interval change did not provoke a dishabituation reaction, but responses to the tones after the long intervals were reliably enhanced. However, AVP did not increase the reaction to stimulus mismatch. It is concluded that autonomic indicators of the habituation of the OR remain unaffected by AVP.     

Antinociceptive effects of intraventricular or systemic administration of vasopressin in the rat

The effects of intraventricular administration of lysine-vasopressin on pain sensitivity in the rat were determined in the tail-flick test. Vasopressin (16–100 μg) was found to induce potent and dose-dependent antinociceptive actions, lasting up to one hour. An additional experiment demonstrated that analgesia induced by vasopressin was not blocked by naloxone, suggesting that this analgesia is independent of opiate receptor systems. Vasopressin was also found to be equally effective in elevating tail-flick latency after systemic administration. These results, together with others, suggest a possible role of vasopressin systems in the regulation of pain sensitivity.     

Potent and selective oxindole-based vasopressin 1b receptor antagonists with improved pharmacokinetic properties

Herein we report the discovery of a novel series of vasopressin 1b (V1b) receptor antagonists, starting from potent but metabolically labile oxindole SSR149415. Masking the proline N,N-dimethyl amide moiety as an oxazole and attaching a benzylic amine moiety to the northern phenyl ring resulted in potent and selective V1b receptor antagonists with improved metabolic stability and improved pharmacokinetic properties in rat. Compound 18c was found to be efficacious in a rat model of anti-depressant activity.     

ACTH,cortisol and glucose responses after administration of vasopressin in cattle and sheep

The present study compared the effects of vasopressin on plasma concentrations of corticotropin, cortisol and glucose in cattle and sheep. After intravenous injection of 1, 0.1 and 0.01 g vasopressin per kg body weight, the plasma vasopressin concentration increased proportionally to the injected dose, and this increase was similar in cattle and sheep. Doses of 1 and 0.1 g per kg body weight of vasopressin triggered significant responses of corticotropin, cortisol and glucose in cattle and sheep. The corticotropin response to both doses was significantly greater in sheep, whereas the glucose response was greater in cattle. The cortisol response did not differ between species. The lowest dose of vasopressin (0.01 g per kg body weight) still induced a significant cortisol response without a substantial effect on plasma corticotropin, suggesting that a direct action of vasopressin on the adrenals may contribute to the observed cortisol response. The results demonstrate that vasopressin increases plasma levels of corticotropin, cortisol and glucose in cattle, as it does in sheep, but the intensities of the corticotropin and glucose responses to vasopressin differ between cattle and sheep. The reasons for these differences remain to be clarified.Abbreviations ACTH corticotropin - AVP vasopressin - bw body weight     

Synthesis and SAR studies of novel 2-(4-oxo-2-aryl-quinazolin-3(4H)-yl)acetamide vasopressin V1b receptor antagonists

Synthesis and structure-activity relationships (SAR) of a novel series of vasopressin V_1b (V₃) antagonists are described. 2-(4-Oxo-2-aryl-quinazolin-3(4H)-yl)acetamides have been identified with low nanomolar affinity for the V_1b receptor and good selectivity with respect to related receptors V_1a, V₂ and oxytocin (OT). Optimised compound 12j demonstrates a good pharmacokinetic profile and activity in a mechanistic model of HPA dysfunction.     

Failure of posttrial administration of vasopressin analogue (DDAVP) to influence memory in healthy, young, male volunteers

The effects of intranasal treatment with DDAVP on healthy, male volunteers was assessed. Subjects were asked to learn prose passages and then were given either 60 μg of DDAVP or saline in a double-blind procedure. Subjects were then asked to recall the passages after a 24-h delay. Treatment had no effect on recall of passages. This suggests that treatment with vasopressin affects acquisition rather than consolidation of newly learned information.     

An exploration of the effects of L- and D-tetrahydroisoquinoline-3-carboxylic acid substitutions at positions 2,3 and 7 in cyclic and linear antagonists of vasopressin and oxytocin and at position 3 in arginine vasopressin

We have investigated the effects of mono-substitutions with the conformationally restricted amino acid, 1,2,3,4 tetrahydroisoquinoline-3-carboxylic acid (Tic) at position 3 in arginine vasopressin (AVP), at positions 2, 3 and 7 in potent non-selective cyclic AVP V₂/V_1a antagonists, in potent and selective cyclic and linear AVP V_1a antagonists, in a potent and selective oxytocin antagonist and in a new potent linear oxytocin antagonist Phaa-D -Tyr(Me)-Ile-Val-Asn-Orn-Pro-Orn-NH₂ (10). We report here the solid-phase synthesis of peptide 10 together with the following Tic-substituted peptides: 1, [Tic³]AVP; 2, d(CH₂)₅[D -Tic²]VAVP; 3, d(CH₂)₅[D -Tyr(Et)²Tic³]VAVP; 4, d(CH₂)₅[Tic²Ala-NH₂⁹]AVP; 5, d(CH₂)₅[Tyr(Me)², Tic³, Ala-NH₂⁹]AVP; 6, d(CH₂)₅ [Tyr(Me)², Tic⁷]AVP; 7, Phaa-D -Tyr(Me)-Phe-Gln-Asn-Lys-Tic-Arg-NH₂; 8, desGly-NH₂,d(CH₂)₅[Tic²,Thr⁴]OVT; 9, desGly-NH₂d(CH₂)₅[Tyr(Me)²Thr⁴, Tic⁷]OVT; 11, Phaa-D-Tic-Ile-Val-Asn-Orn-Pro-Orn-NH₂, using previously described methods. The protected precursors were synthesized by the solid-phase method, cleaved, purified and deblocked with sodium in liquid ammonia to give the free peptides 1–11 which were purified by methods previously described. Peptides 1–11 were examined for agonistic and antagonistic potency in oxytocic (in vitro, without Mg²⁺) and AVP antidiuretic (V₂-receptor) and vasopressor (V_1a-receptor) assays. Tic³ substitution in AVP led to drastic losses of V₂, V_1a and oxytocic agonistc activities in peptide 1.L - and D -Tic² substitutions led to drastic losses of anti-V₂/anti-V_1a and anti-oxytocic potencies in peptides 2, 4, 8 and 11 (peptide 2 retained substantial anti-oxytocic potency; pA₂ = 7.25 ± 0.25). Whereas Tic³ substitution in the selective V_1a antagonist d(CH₂)₅[Tyr(Me)², Ala-NH₂⁹]APV(C) led to a drastic reduction in anti-V_1a potency (from anti-V_1a pA₂) 8.75 to 6.37 for peptide 5, remarkably, Tic³ substitution in the V₂/V_1a antagonist d(CH₂)₅[D -Tyr(Et)²]VAVP(B) led to full retention of anti-V₂ potency and a 95% reduction in anti-V_1a potency. With an anti-V₂ pA₂ = 7.69 ± 0.05 and anti-V_1a pA₂ = 6.95 ± 0.03, d(CH₂)₅[D -Tyr(Et)²,Tic³]VAVP exhibits a 13-fold gain in anti-V₂/anti-V_1a selectivity compared to (B). Tic⁷ substitutions are very well tolerated in peptides 6, 7 and 9 with excellent retention of the characteristic potencies of the parent peptides. The findings on the effects of Tic³ substitutions reported here may provide promising leads to the design of more selective and possibly orally active V₂ antagonists for use as pharmacological tools and as therapeutic clinical agents for the treatment of the syndrome of the inappropriate secretion of antidiuretic hormone (SIADH).     

Opposite effects of intraventricular and intracisternal administration of vasopressin on blood pressure in rats

Lysine-8-vasopressin (LVP) was injected into the lateral ventricle (ICV) or into the cisterna magna (c.m.) of ether-anesthetized rats. ICV injection of LVP decreased the blood pressure (BP), whereas c.m. administration increased it. The opposite effects of ICV versus c.m. administration of the peptide might be related to differences in brainstem versus limbic-midbrain structures in the regulation of blood pressure, and suggest that both mechanisms can be influenced by vasopressin.     

Sentence memory affected by vasopressin analog (DDAVP) in cross-over experiment

DDAVP has been shown to facilitate memory, especially retrieval, in humans. Healthy young male adult subjects received DDAVP (60 micrograms) in a cross-over design with a one-week interval between sessions. Results indicated that DDAVP improved immediate memory during the first but not the second testing session, particularly for low-verbal subjects. Treatment with DDAVP also facilitated delayed (one-week) recall in the opposite group, a cross-over interaction that suggests a retrieval locus for the DDAVP effect. Furthermore, since DDAVP improved immediate memory more for low-verbal subjects and delayed memory more for high-verbal subjects, it appears that individual difference factors will be important in understanding the effects of vasopressin on memory.     

Oral administration of cholecystokinin receptor antagonists increase feed intake in rainbow trout

Individual immature rainbow trout consumed 1–2% body weight per day, but significantly more ( P < 0·001) when fed by hand than by demand feeder. When treated with CCK antagonists (L 364, 718; 100 μg kg⁻¹ on day 12 or SR 27, 897; 50 μg kg⁻¹ on day 16), the fish ate significantly more than their mean daily intake on the other days of the experiment. This increase in feed intake was affected by the feeding technique: hand-fed fish increased by 70–80% their feed intake while in demand-fed fish the increase was significantly less (50–60%). However, the increase in feed intake observed on days 12 and 16 was identical for both drugs used.     

Effects of vasopressin on electrolyte transport in lizard intestine

Summary Vasopressin applied serosally had no effect on electrical parameters and unidirectional Na and Cl fluxes across anin vitro short circuited preparation of lizard ileum. Short circuit current (Isc) and transmural potential difference (PD) across colon were decreased by vasopressin and increased by cyclic AMP. Vasopressin increased the mucosal-to-serosal flux of sodium and chloride across short circuited colon. Cyclic AMP had no effect on the rate of Na absorption but reversed Cl absorption to secretion. Vasopressin enhanced the net absorption of water across the colon but had no effect on absorption across ileum. Cyclic AMP activity in homogenates of colon was not altered by vasopressin but was increased by theophylline. It is concluded that the colonic response of the lizard colon to vasopressin is mediated by a noncyclic AMP mechanism.     

Electronmicroscopic immunocytochemical study on the vasopressin-containing neurons of the thirsting rat

Summary Whereas in thirsting animals the perikarya of the nucleus supraopticus are nearly empty of neurosecretory granules as evidenced by electron microscopic observation, the perikarya are heavily stained by light microscopic immunohistochemical staining. In an attempt to discover the substrate responsible for the positive immunohistochemical staining in thirsting rats, the neurons of the supraoptic nucleus of normal and long-term thirsting animals were compared by electron microscopic immunocytochemistry (indirect PAP-method). In controls all parts of the vasopressin-synthesizing neuron are filled with elementary granules which render a positive and uniform reaction after immunostaining with the indirect PAP-method. The positively reacting fibers in the external zone of the median eminence contain smaller granules than those of the tractus supraoptico-hypophyseus. Within the nucleus suprachiasmaticus, no positive reaction after immunostaining was found. In long-term thirsting animals PAP-complexes as markers of vasopressin are located over the ergastoplasm and over the few small elementary granules. The processes within the nucleus supraopticus and the ballooned axons in the internal zone of the median eminence exhibit free, i.e. non granule-bound, PAP-complexes. Findings in the nucleus suprachiasmaticus and the median eminence of thirsting animals correspond to those in controls. The neurohypophysis is almost completely devoid of PAP-labeled elementary granules.From these results it can be concluded that during thirst vasopressin synthesis is increased in the ergastoplasm and that the hormone is transported partly in a non granule-bound form. Direct contacts between neurosecretory cells and the basal lamina are found more often in thirst-stressed animals and are typical of neurohemal regions. It is discussed whether these neurohemal regions may develop transitionally under stress.Supported by the Deutsche Forschungsgemeinschaft (Grant Nr. Kr 569/1) and Stiftung Volkswagenwerk. This work was presented in part at the 72nd meeting of the Anatomische Gesellschaft, Aachen 1977     

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 15 mm 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 100 ng/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.     

Regulation of hippocampal corticosterone receptors by a vasopressin analogue

Vasopressin can alter hippocampal corticosterone receptor number, as a congenital absence of a peptide in the Brattleboro rat results in decreased concentrations of the receptor; this deficit can be reversed with des-glycinimide arginine vasopressin (dGVP), a centrally-acting VP analogue. We examined whether vasopressin might regulate less dramatic fluctuations of hippocampal corticosterone receptor number in the normal rat. Administration of dGVP failed to alter the rate of or extent of down- or up-regulation of hippocampal corticosterone receptors by circulating corticosterone, suggesting that alteration of neural VP content is not a mediating step in such regulation.     

Behavioral and biochemical responses of mice to the intraventricular administration of ACTH analogs and lysine vasopressin.

ACTH_1?24, ACTH_4?10, ACTH_4?10(D-phe), lysine vasopressin (LVP) or an amino acid mixture were administered to mice using bilateral intraventricular injections (5×10^?9 moles per mouse). Behavioral observations were made for the subsequent 85 minutes, and the incorporation of subcutaneously injected [³H]lysine into brain proteins assayed for the last 10 minutes of this period. Mice injected with ACTH_1?24 showed the previously reported stretching and yawning syndrome, an effect also observed with ACTH_4?10(D-phe) but less often. These same peptides also induced a pronounced increase in the proportion of time mice spent grooming. LVP caused a dramatic hyperactivity; mice so injected moved continously about the cage occasionally eating or grooming, but were never still. Injection with ACTH_1?24 or ACTH_4?10(D-phe), but not ACTH_4?10 or LVP, caused significant increases in the incorporation of [³H]lysine into brain protein.     

The oxidation of oxytocin and vasopressin by peroxidase/H2O2 system

Summary Oxytocin and vasopressin are oxidized by horseradish peroxidase and by lactoperoxidase, in the presence of hydrogen peroxide. Spectrophotometric measurements are indicative of the formation of dityrosine. Kinetic parameters indicate that the affinity of horseradish peroxidase is slightly higher for oxytocin with respect to vasopressin and that the two hormones are better substrates for both peroxidases than free tyrosine.     

The effect of chronic vs. acute injection of vasopressin on animal learning and memory

The effect of chronic and acute treatment with DDAVP, a vasopressin analog, was studied in 2 month old male rats, using an active avoidance test in a shuttle box. The experiment lasted 6 weeks: an acquisition period of 4 weeks and an extinction period of 2 weeks. Rats were treated one hour before behavioral testing 3 times a week for 6 weeks with either DDAVP 20 micrograms/rat/day for the whole period (chronic group) or with DDAVP for the first week and again once only on the first day of the extinction period (acute group) or with saline. Chronic treatment with DDAVP resulted in better acquisition and in a marked retardation of extinction compared with the acute treatment group. These results were obtained both in normal rats and in rats pretreated at age 5 days of life with intracisternal 6-OH dopamine.