Arginine vasopressin and a vasopressin antagonist peptide: Opposite effects on extinction of active avoidance in rats

Systemic injection of arginine vasopressin (AVP) (1 μ/rat) significantly prolonged extinction of a pole-jump, active avoidance response in rats; lateral ventricular injection of 1000-fold less AVP (1 ng/rat) produced similar results. A new AVP analogue, [1-deaminopenicillamine-2-(O-methyl)-tyrosine]arginine vasopressin (dPTyr-(Me)AVP), is known to antagonize behavioral and vascular effects of exogenous AVP at molar ratios of 5:1. At a dose of 100 μ/rat (subcutaneously) dPTyr-(Me)AVP produces, by itself, a behavioral effect opposite to that of exogenous AVP, namely a facilitation of extinction. Injections of dPTyr-(Me)AVP into the lateral ventricle were ineffective except at a dose of 10 μg/rat. These results confirm previous reports of the effect of vasopressin on delaying extinction of avoidance behavior, but suggest a site of action distant from the lateral ventricle.     

Role of intracerebroventricular vasopressin in the development of stress-induced gastric lesions in rats

We investigated whether arginine vasopressin (AVP) has a central influence on the development of gastric mucosal lesions evoked by restraint-cold stress in rats. AVP and vasopressin V1 receptor antagonist were injected intracerebroventricularly (i.c.v.) and the rats were exposed to restraint-cold stress for five hours. After decapitation the stomachs were examined for gastric mucosal lesions which were evaluated according to an ulcer score. Three different doses of AVP and V1 receptor antagonist were administered in order to investigate the effects of exogenous and endogenous AVP on stress-induced gastric mucosal lesions. The intensity of gastric mucosal lesions was reduced when exogenous AVP was injected intracerebroventricularly. On the other hand, vasopressin V1 receptor antagonist, which was administered by the same route, augmented gastric mucosal lesions. Our findings indicate that AVP, injected centrally, plays a role in preventing the formation of gastric mucosal lesions induced by stress via a central V1 receptor.     

Effects of peripherally injected vasopressin and des-glycinamide vasopressin on the extinction of a spatial learning task in rats

An elevated eight-arm radial maze was employed to study the effects of neuropeptide administration on the spatial learning abilities of food-deprived rats. Following 18 days of reinforced training, each animal was briefly exposed to the maze with no food available in any of the eight food-cups. Immediately after this preliminary trial, animals were injected with a single subcutaneous dose of either saline, arginine vasopressin (AVP: 1.0 or 5.0 micrograms/kg), or an AVP analog with only weak endocrinological activity, des-gly-arginine vasopressin (DG-AVP: 1.0, 5.0 or 10.0 micrograms/kg). Additional extinction trials were conducted at 2, 4, 6 and 8 h post-injection. These tests consisted of individually placing an animal on the empty maze and recording the number of arms chosen in a 5-min period. In this situation, animals learn that food is no longer present in the maze and, consequently, extinguish responding. Vasopressin potentiated this radial maze extinction behavior while DG-AVP produced behavioral results directionally opposite to those predicted by a memory facilitation hypothesis. In a subsequent experiment, vasopressin had no effects on unconditioned locomotor activity measured 2 and 4 h post-injection. These results suggest that: vasopressin improved the learning that occurred during extinction of conditioned appetitive behaviors, these vasopressin effects on conditioned behavior were independent of any unconditioned, sedative or non-specific actions of the peptide, and peripheral endocrinological responses may be necessary to demonstrate memory-enhancing effects following peripherally administered AVP.     

Central injections of arginine vasopressin prolong extinction of active avoidance

Behavioral and physiological effects of arginine vasopressin (AVP) were examined following intracerebroventricular (ICV) injection in the rat. ICV injections prolonged extinction of active avoidance at doses of 1.0 and 10.0 ng/rat and this effect was blocked by peripheral injection of the vasopressor antagonist of vasopressin [dPtyr(Me)AVP] at a dose of 30 micrograms/kg (SC). However, 1.0 ng of AVP ICV failed to alter systemic blood pressure and also failed to produce taste aversions in a one or two bottle test. Results suggest that central AVP has a central action independent of systemic changes in blood pressure, but that the receptor mediating this action is functionally similar to the AVP V1 (vasopressor) receptor.     

Peripheral mechanisms involved in the pressor and bradycardic effects of centrally administered arachidonic acid

In the current study, we aimed to determine the cardiovascular effects of arachidonic acid and peripheral mechanisms mediated these effects in normotensive conscious rats. Studies were performed in male Sprague Dawley rats. Arachidonic acid was injected intracerebroventricularly (i.c.v.) at the doses of 75, 150 or 300 microg and it caused dose- and time-dependent increase in mean arterial pressure and decrease in heart rate in normal conditions. Maximal effects were observed 10 min after 150 and 300 microg dose of arachidonic acid and lasted within 30 min. In order to evaluate the role of main peripheral hormonal mechanisms in those cardiovascular effects, plasma adrenaline, noradrenaline, vasopressin levels and renin activity were measured after arachidonic acid (150 microg; i.c.v.) injection. Centrally injected arachidonic acid increased plasma levels of all these hormones and renin activity. Intravenous pretreatments with prazosin (0.5 mg/kg), an alpha1 adrenoceptor antagonist, [beta-mercapto-beta,beta-cyclopentamethylenepropionyl1, O-Me-Tyr2-Arg8]-vasopressin (10 microg/kg), a vasopressin V1 receptor antagonist, or saralasin (250 microg/kg), an angiotensin II receptor antagonist, partially blocked the pressor response to arachidonic acid (150 microg; i.c.v.) while combined administration of these three antagonists completely abolished the effect. Moreover, both individual and combined antagonist pretreatments fully blocked the bradycardic effect of arachidonic acid. In conclusion, our findings show that centrally administered arachidonic acid increases mean arterial pressure and decreases heart rate in normotensive conscious rats and the increases in plasma adrenaline, noradrenaline, vasopressin levels and renin activity appear to mediate the cardiovascular effects of the drug.     

Pinealectomy blocks modulation of active avoidance by central vasopressin application in rats

The inter-relationship between central vasopressin and the pineal gland in the modulation of active avoidance behavior was investigated. In sham-operated (SO) rats, intracerebroventricular (i.c.v) application of 10 ng arginine vasopressin (AVP) after both the last acquisition and the first extinction trials prolonged the extinction of the active avoidance response; application of 50 ng of the V1 antagonist, d(CH2)5Tyr(Me)AVP (AAVP) was without effect in both experiments. In contrast to the SO in pinealectomized (PX) rats neither AVP nor AAVP influenced the extinction of the avoidance response. Intraseptal infusion of 200 pg AVP or 5 ng AAVP either after the last acquisition or the first extinction trial was without effect in both SO and PX rats. Comparison of the acquisition trials revealed no differences between SO and PX rats.     

Arginine vasopressin does not mediate heat loss in the tail of the rat

It has been reported that hypothermia induced by arginine vasopressin (AVP) is brought about by a coordinated response of reduced thermogenesis in brown adipose tissue (BAT) and increased heat loss through the tail of rats. However, it is well known that AVP is one of the strongest peripheral vasoconstrictors. Whether the AVP-induced hypothermia is associated with an increase in heat loss through the tail is questionable. Therefore, the present study assessed the relationship between the effects of AVP on tail skin temperature and the induced hypothermic response, and to determine if peripheral AVP administration increases heat loss from the tail. Core, BAT and tail skin temperature were monitored by telemetry in male Sprague–Dawley rats before and after intraperitoneal administration of AVP or vasopressin receptor antagonist. We also analyzed simultaneously of the time-course of AVP-induced hypothermic response and its relationship with changes in BAT temperature, and effect of AVP on grooming behavior. The key observations in this study were: (1) rats dosed with AVP induced a decrease in heat production (i.e., a reduction of BAT thermogenesis) and an increase of saliva spreading for evaporative heat loss (i.e., grooming behavior); (2) AVP caused a marked decrease in tail skin temperature and this effect was prevented by the peripheral administration of the vasopressin V1a receptor antagonist, suggesting that exogenous AVP does not increase heat loss in the tail of rats; (3) the vasopressin V1a receptor antagonist could elevate core temperature without affecting tail skin temperature, suggesting that endogenous AVP is involved in suppression of thermogenesis, but not mediates heat loss in the tail of rats. Overall, the present study does not support the conclusion of previous reports that AVP increased tail heat loss in rats, because AVP-induced hypothermia in the rat is accompanied by a decrease in tail skin temperature. The data indicate that exogenous AVP-induced hypothermia attributed to the suppression of thermoregulatory heat production and the increase of saliva spreading for evaporative heat loss.     

Different peripheral and central antagonistic activity of new glutaramic acid derivatives on satiety induced by cholecystokinin in rats

New glutaramic acid derivatives with cholecystokinin antagonistic activity were evaluated for their capacity to inhibit the satiety effect induced in the rat by intraperitoneal (i.p.) injection of cholecystokinin octapeptide (CCK-8). The most active compound, CR 1409, is about 4000 times more potent than proglumide when injected peripherally (i.p.). This compound competitively inhibits the action of CCK-8 at the receptor responsible for the satiety effect. In contrast, CR 1409, i.p. or intracerebroventricularly (i.c.v.) injected does not exhibit antagonistic effects when CCK-8 is administered i.c.v., confirming the existence of at least two different populations of CCK receptors.     

Dose-dependent effects of L-carnosine on the renal sympathetic nerve and blood pressure in urethane-anesthetized rats

The physiological function of L-carnosine (beta-alanyl-L-histidine) synthesized in mammalian muscles has been unclear. Previously, we observed that intravenous (i.v.) injection of L-carnosine suppressed renal sympathetic nerve activity (RSNA) in urethane-anesthetized rats, and L-carnosine administered via the diet inhibited the elevation of blood pressure (BP) in deoxycorticosterone acetate salt hypertensive rats. To identify the mechanism, we examined effects of i.v. or intralateral cerebral ventricular (l.c.v.) injection of various doses of L-carnosine on RSNA and BP in urethane-anesthetized rats. Lower doses (1 microg i.v.; 0.01 microg l.c.v.) of L-carnosine significantly suppressed RSNA and BP, whereas higher doses (100 microg i.v.; 10 microg l.c.v.) elevated RSNA and BP. Furthermore, we examined effects of antagonists of histaminergic (H1 and H3) receptors on L-carnosine-induced effects. When peripherally and centrally given, thioperamide, an H3 receptor antagonist, blocked RSNA and BP decreases induced by the lower doses of peripheral L-carnosine, whereas diphenhydramine, an H1 receptor antagonist, inhibited increases induced by the higher doses of peripheral L-carnosine. Moreover, bilateral lesions of the hypothalamic suprachiasmatic nucleus eliminated both effects on RSNA and BP induced by the lower (1 microg) and higher (100 microg) doses of peripheral L-carnosine. These findings suggest that low-dose L-carnosine suppresses and high-dose L-carnosine stimulates RSNA and BP, that the suprachiasmatic nucleus and histaminergic nerve are involved in the activities, and that L-carnosine acts in the brain and possibly other organs.     

The cyclized C-terminal dipeptide of arginine vasopressin: Metabolic stability and antagonism of puromycin-induced amnesia

The cyclized derivative of the C-terminal dipeptide of arginine vasopressin (AVP), cyclo(Arg-Gly), can, when administered peripherally, block puromycininduced amnesia in mice. The potency and time course of action of this peptide are very similar to that of the parent hormone, AVP. Radioactively labelled cyclo(Arg-Gly), injected sc, was found to be degraded mainly by kidney and liver, and both intact peptide and degradation products reached the brain. However, cyclo(Arg-Gly) injected directly into brain was stable for up to 24 hr. The disappearance of cyclo(Arg-Gly) from plasma and brain was biphasic, with halflives longer than that reported for AVP. The results suggest that cyclo(Arg-Gly), formed in vivo from AVP, could contribute to the long-term effects of AVP in the CNS. However, not all of the actions of the hormone can be attributed to formation of longer-acting derivatives, and it is postulated that separate receptors may exist in brain for the neurohypophyseal hormones and their active fragments.     

Antipyretic effect of arginine vasotocin in toads

Arginine vasotocin (AVT) is a nonmammalian analog of the mammalian hormone arginine vasopressin (AVP). These peptides are known for their antidiuretic and pressor effects. More recently, AVP has been recognized as an important antipyretic molecule in mammals. However, no information exists about the role of AVT in febrile ectotherms. We tested the hypothesis that AVT is an antipyretic molecule in the toad Bufo paracnemis. Toads equipped with a temperature probe were placed in a thermal gradient, and preferred body temperature was recorded continuously. A behavioral fever was observed after lipopolysaccharide (LPS) was injected systemically (200 microg/kg). Systemically injected AVT (300 pmol/kg) alone caused no significant change in body temperature, but abolished LPS-induced fever. Moreover, a smaller dose of AVT (10 pmol/kg), which did not affect LPS-induced fever when injected peripherally, abolished fever when injected intracerebroventricularly. We therefore conclude that AVT plays an antipyretic role in the central nervous system, by means of behavior, in an ectotherm, a fact consistent with the notion that AVT/AVP elicits antipyresis by reducing the thermoregulatory set point.     

Central vasopressin in the modulation of catecholamine release in conscious rats

Neurons containing arginine vasopressin (AVP) have been shown to project from the paraventricular nucleus of the hypothalamus to the nucleus tractus solitarius (NTS) in the medulla. We investigated whether AVP acts in brain stem regions to influence sympathoadrenal outflow. Cannulae were implanted into the fourth ventricle of rats 7 days prior to the experiment. The effects of intracerebroventricular (icv) injections of AVP, the vehicle, and AVP antagonist, d(CH2)5Tyr(Me)AVP, on mean arterial pressure (MAP) and plasma noradrenaline (NA) and adrenaline (A) levels were determined in conscious unrestrained rats. Injections of AVP (icv, 23 and 73 ng/kg) but not the vehicle increased MAP and plasma NA and A levels. In contrast, iv injection of AVP increased MAP but decreased plasma concentrations of A and NA. The pressor response to icv injection of AVP was abolished by prior icv injection of AVP antagonist. Injection of AVP antagonist (icv, 0.5 and 1.5 microgram/kg) had no effect on MAP or plasma NA or A levels. These results show that centrally injected AVP activates sympathoadrenal outflow, possibly via an inhibition of baroreceptor reflexes. Since centrally administered AVP antagonist did not influence MAP or plasma NA or A levels, it appears that endogenously released AVP does not have a tonic influence on central cardiovascular reflex system in conscious, unrestrained rats.     

Effect of vasopressin and V1 receptors blockade on hypotensive action of ANP in normotensive (WKY) and spontaneously hypertensive rats.

The aim of the study was to find out whether vasopressin (AVP) modifies hypotensive and heart rate accelerating effects of atrial natriuretic peptide (ANP) in normotensive (WKY) and spontaneously hypertensive (SHR) conscious rats. The effect of i.v. administration of 1; 2 and 4 micrograms of ANP on blood pressure (MP) and heart rate (HR) was compared during i.v. infusion of 0.9% NaCl (NaCl), NaCl+AVP (1.2 ng kg-1 min-1) and NaCl+dEt2AVP (V1 receptors antagonist, 0.5 microgram kg-1 min-1). AVP increased MP in SHR and WKY and decreased HR in SHR. V1 antagonist decreased MP and increased HR only in SHR. In SHR ANP decreased MP and increased HR during NaCl, AVP and V1 antagonist infusion. In WKY these effects were observed only during AVP administration. In each experimental situation hypotension and tachycardia induced by ANP were greater in SHR than in WKY. In both strains ANP induced changes in MP and HR were enhanced during AVP in comparison to NaCl infusion. V1 antagonist did not modify effects of ANP in WKY and SHR. The results indicate that ANP abolishes hypertensive response induced by blood AVP elevation and that the basal levels of endogenous vasopressin acting through V1 receptors does not interfere with hypotensive action of ANP neither in WKY nor in SHR.     

Antagonism of effects of vasopressin (AVP) on inhibitory avoidance by a vasopressin antagonist peptide [dPtyr(Me)AVP]

After training in two different passive avoidance tasks, the platform box of Ader and De Wied (1972) and the Jarvik box of Jarvik and Kopp (1967), rats injected with vasopressin immediately following the training trial showed a significant enhancement of retention 24 hours later. This vasopressin effect was reversed by high doses of the vasopressor antagonist, dPtyr(Me) AVP. These results support the hypothesis that the visceral afferent signals may be involved in the apparent memory-enhancing effects of AVP, but the high doses of antagonist required suggest that factors other than a simple reversal of the pressor effects of AVP may be important.     

Centrally administered galanin modifies vasopressin and oxytocin release from the hypothalamo-neurohypophysial system of euhydrated and dehydrated rats.

Galanin (Gal) as a neuropeptide with widespread distribution in the central nervous system may be involved in the mechanisms of vasopressin (AVP) and oxytocin (OT) release from the hypothalamo-neurohypophysial system. Vasopressin and oxytocin content in the hypothalamus and neurohypophysis as well as plasma level of both neurohormones were studied after galanin treatment in euhydrated and dehydrated rats. In not dehydrated rats intracerebroventricular (i.c.v.) injections of Gal did not affect the hypothalamic and neurohypophysial OT content, however, distinctly increased plasma OT concentration. In the same animals Gal diminished the hypothalamic AVP content but was without the effect on neurohypophysial AVP storage; plasma AVP level then raised. Galanin, administered i.c.v. to rats deprived of water, distinctly inhibited AVP and OT release from the hypothalamo-neurohypophysial system. Simultaneously, plasma AVP and OT level was significantly diminished after Gal treatment in dehydrated rats. These results suggest that modulatory effect of galanin on vasopressin and oxytocin release depends on the actual state of water metabolism. Gal acts as an inhibitory neuromodulator of AVP and OT secretion under conditions of the dehydration but stimulates this process in the state of equilibrated water metabolism.     

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.     

Long-term facilitation of social recognition in rats by vasopressin related peptides: a structure-activity study.

The effect of several vasopressin-related peptides was investigated in the social recognition paradigm, that consists of two successive encounters of a resident and a juvenile rat. The decrease of social investigation time of the resident rat during the second encounter served as a measure for social recognition. Single administration (3.0 micrograms, s.c.) of the vasopressin (AVP)-related peptides AVP-(1-8), AVP-(1-7) or AVP-(1-6), injected just after the first encounter, resulted in social recognition after 24 hours. Such an effect was not observed after placebo treatment or an injection with AVP-(1-5), [pGlu4, Cyt6]AVP-(4-8), [pGlu4, Cyt6]-AVP-(4-9), AVP-(7-9) or oxytocin-(1-6)-NH2. The peptide AVP-(1-6) was also active when administered in a dose of 0.3 micrograms in contrast to other peptides. Thus, vasopressin related peptides induce long term facilitation of social recognition and this action resides in the covalent ring structure of vasopressin. This effect resembles the vasopressin-induced facilitation of particular memory processes, as revealed with other behavioral paradigms.     

Effect of vasotocin on locomotor activity in bullfrogs varies with developmental stage and sex

Although neurohypophysial peptides are present in many regions of the developing and adult bullfrog (Rana catesbeiana) brain, the function of these peptides remains unclear. To investigate possible behavioral actions, we examined locomotor activity following peptide injection in bullfrogs at various developmental stages. An intraperitoneal (ip) injection of arginine vasotocin (AVT) in tadpoles (stages V, X, or XVII) produced an immediate and dose-dependent inhibition of locomotor activity. On the other hand, AVT stimulated activity when administered ip to juvenile or adult female bullfrogs, but did not influence activity in juvenile or adult males. The minimum effective dose of AVT, when injected directly into the brain of tadpoles, was 100-fold less than that observed when injected ip, suggesting a central nervous system site of action for this peptide. A vasopressin receptor antagonist (d(CH2)5[Tyr(Me)2]AVP administered ip or icv) significantly increased locomotor activity in tadpoles, compared to controls. Oxytocin, vasopressin, and AVP4-9 inhibited activity in tadpoles while mesotocin, des Gly(NH2)AVP, and pressinoic acid had no significant effect. Injection of PGF2 alpha also significantly decreased activity levels in tadpoles. However, pretreatment of tadpoles with indomethacin, a prostaglandin synthesis inhibitor, did not prevent the behavioral effects of AVT, suggesting that prostaglandin synthesis is not required for this response. In summary, AVT influenced locomotor activity in bullfrog tadpoles and female frogs. This effect shifted during development from an inhibitory action in tadpoles to a stimulatory effect in metamorphosed female frogs. The effect of AVT on juvenile and adult frog locomotion was sexually dimorphic, as this peptide altered female behavior but not male behavior.     

Effects of intracerebroventricularly injected glucagon-like peptide-1 on cardiovascular parameters; role of central cholinergic system and vasopressin

We aimed to investigate the effects of intracerebroventricularly (i.c.v.) injected glucagon-like peptide-1 (GLP-1) on blood pressure and heart rate, and whether central cholinergic system and vasopressinergic system play roles in these effects. Male Wistar albino rats were used throughout the experiments. Blood pressures and heart rates were observed before and for 30 min following drug injections. i.c.v. GLP-1 (100, 500 and 1000 ng/10 microl) caused a dose-dependent increase in both blood pressure and heart rate. Nicotinic receptor antagonist mecamylamine (25 microg/10 microl, i.c.v.) and muscarinic receptor antagonist atropine (5 microg/10 microl, i.c.v.) prevented the stimulating effect of GLP-1 on blood pressure. The effect of GLP-1 on heart rate was blocked only by mecamylamine. The V1 receptor antagonist of vasopressin (B-mercapto B, B-cyclopentamethylenepropionyl, O-Me-Tyr,Arg)-vasopressin (10 microg/kg), that was applied intraarterially, only prevented the effect of GLP-1 on blood pressure, but did not show any effect on heart rate. Our data indicate that i.c.v. GLP-1 increases blood pressure and heart rate, and stimulation of central nicotinic and partially muscarinic receptors and vasopressinergic system play a role in the effects of i.c.v. GLP-1 on blood pressure. The effect of GLP-1 on heart rate may be partially due to stimulation of central nicotinic receptors.     

Regulation of gastrointestinal function by multiple opioid receptors

Agonist and antagonist drugs possessing selectivity for individual types of opioid receptors have been employed in vitro and in vivo to determine the mechanisms by which opioids regulate gastrointestinal functions. Selective mu opioid agonists given by intracerebroventricular (i.c.v.) injection, by intrathecal (i.t.) injection, or by peripheral (s.c. or i.v.) injection in rats or mice decreased gastrointestinal transit and motility, inhibited gastric secretion, and suppressed experimentally-induced diarrhea. Selective delta agonists, by contrast, inhibited gastrointestinal transit after i.t., but not after i.c.v. or s.c. administration. Delta agonists also did not alter gastric secretion after i.c.v. or s.c. injection. However, delta agonists exhibited antidiarrheal effects after i.c.v., i.t., or s.c. administration. Kappa agonists given i.c.v. had no effect on gastrointestinal transit in rats or mice or on gastric secretion in rats, but exhibited antidiarrheal effects in mice. The kappa agonist U-50, 488H given peripherally increased gastric acid secretion. Different types of opioid receptors in different anatomical sites influence differently gastrointestinal motility and propulsion, gastric secretion, and mucosal transport. Brain, spinal cord, enteric neural and smooth muscle opioid receptors represent chemosensitive sites for regulation of gastrointestinal function.