Vasopressin release during nonhypotensive hemorrhage and angiotensin II infusion.

These experiments were designed to determine whether angiotensin II (AII) could potentiate the increase in plasma vasopressin (ADH) concentration produced by continuous, nonhypotensive hemorrhage in nephrectomized dogs. Infusion of AII (10 ng/kg.min) into a common carotid artery in nonbled dogs did not increase plasma ADH levels, suggesting that increases in carotid arterial plasma AII concentration alone do not stimulate an increase in ADH release. Subsequently, nephrectomized dogs subjected to nonhypotensive hemorrhage (0.44 ml/kg.min) were infused as follows: 0.9% saline intravenously, AII (10 ng/kg.min) intravenously, or AII (10 ng/kg.min) into the carotid. The Plasma ADH concentration increased in all three groups of dogs during hemorrhage. Although the AII-infused dogs demonstrated significant increases in plasma ADH levels earlier during hemorrhage, these changes were small; there were no statistically significant differences in plasma ADH concentrations among the three groups. These results suggest that increases in plasma AII concentration have little or no significant effect on the volume control of ADH release.     

Vasopressin release induced by intracranial injection of tachykinins is due to activation of central neurokinin-3 receptors

The present study investigated the effect on vasopressin release of the intracerebroventricular injection of tachykinins in rats. The selective neurokinin (NK)-3 receptor agonists [MePhe7]neurokinin B and [Asp5,6MePhe8]substance P(5-11) evoked vasopressin release. Also eledoisin, physalaemin and kassinin, which show good affinity for central NK-3 receptors, released vasopressin. On the other hand, neurokinin A, substance P and the selective NK-1 agonist [Pro9,Met(O2)11]substance P were devoid of activity. At doses releasing vasopressin, central injection of NK-3 selective agonists and of the natural tachykinins never produced hypotension. Present results indicate that activation of central NK-3 receptors is involved in vasopressin release induced by tachykinins, and rule out the possibility that the effect might be consequent to hypotension due to passage of tachykinins into the peripheral circulation.     

Vasopressin release and firing of supraoptic neurosecretory neurones during drinking in the dehydrated monkey

A close relationship exists between drinking and the release of vasopressin, the two main factors responsible for the maintenance of body water content. Whereas the participation of peripheral factors, such as oropharyngeal stimulation, seems obvious in the metering of fluid intake and in thirst satiation, very little is known about their influence on vasopressin release. In the present experiments, the influence of drinking on vasopressin release was studied using both biochemical and electrophysiological approaches.In one group of monkeys made thirsty by water deprivation, the subsequent drinking of water during a 5–8 min induced: i) a short-term response, consisting of an abrupt fall in plasma vasopressin concentration which was independent of osmolality, occurred at the time of drinking and was partly reversed after the cessation of drinking, and ii) a longer lasting response, consisting of a slow diminution of plasma vasopressin concentration as the intestinal absorption of water progressed. In another group of thirsty monkeys, extracellular recordings were made during drinking from cells which were identified as neurosecretory neurones of the supraoptic nucleus, a number of them being considered vasopressin secreting on the basis of their phasic pattern of firing. Their firing decreased considerably during the periods of water intake and recovered to control levels immediately after-wards.The decrease in vasopressin release at the onset of water intake, the diminution in the firing rate of the neurones, the short latency and the reversibility of these events after cessation of drinking, suggest that a reflex inhibition of vasopressin-secreting neurones occurs which is probably induced by peripheral stimuli and most likely via oropharyngeal or other visceral receptors. It is postulated that this reflex inhibition of vasopressin release may participate in some active manner in the anticipatory mechanisms of thirst satiation.     

Postingestional modulation of drinking induced in rats by angiotensin II: intragastric infusion and sham drinking studies

The dipsogenic potency of angiotensin II (ANGII, 200 micrograms/kg, SC) was examined after the removal of various postingestional factors. In the first experiment, rats with intragastric catheters were injected SC with ANGII and allowed water to drink. During the induced drinking, either NaCl (1.5 M) or water was injected into the stomach via the catheter at a rate of 0.1 ml for each ml water ingested orally. The water intake was identical in the two conditions. In a second experiment, rats, fitted with gastric fistulas, were administered ANGII and subsequent water intake with fistulas open was compared to that occurring with the fistulas closed. Rats drank more water during the first trial with fistulas open than with fistulas closed. Water intake during subsequent trials with an open fistula rose above that observed on the first trial. In a third experiment, rats with gastric fistulas were offered 0.15 M NaCl to drink. Intake was greater when the fistula was open than when it was closed. Intake of 0.15 M NaCl increased during the second trial with fistula open. Rats drank more 0.15 M NaCl during the first trial with an open fistula in Experiment 3 than those rats given water to drink on their first trial with fistula open in Experiment 2. These data suggest both oropharyngeal and postingestional factors interact in the control of ANGII-induced fluid intake.     

Vasopressin release induced by hemorrhage in the goat

Effects of moderate hemorrhage were studied in normovolemic and hydrated conscious goats. Plasma arginine vasopressin (AVP) in jugular vein blood did not rise in response to bleeding of 8 and 12 ml/kg b.wt. After a blood loss of 16 ml/kg an abrupt and conspicuous rise in plasma AVP (to > 10 times basic level) was seen in 50% of the experiments, whereas no rise in AVP occurred in the remaining experiments. Bleeding at 20 and 24 ml/kg gave a more consistent AVP response. Hydration did apparently not reduce the AVP-responsiveness to bleeding. The plasma vasopressin concentration returned to pre-hemorrhage level about 3 h after bleeding, i.e. before the blood was re-transfused. A minor, and inconsistent rise in plasma renin activity occurred in response to bleeding. Central venous pressure fell during hemorrhage and stayed depressed until the blood was re-transfused. Since the depression was of the same order in all experiments, and was still present when plasma AVP had returned to pre-hemorrhage level, the fall in venous pressure was obviously not the main cause of the AVP-response. However, the pronounced rise in plasma vasopressin was correlated to a fall in the arterial pressure and to hyperventilation. No urge to drink developed during any of the hemorrhage experiments. It is concluded that the goat does not readily respond to hemorrhage with vasopressin liberation. When it happens, pressor amounts of the hormone are released, and a fall in arterial pressure and/or increased stimulation of respiratory chemoreceptors (hypoxia?) appear(s) to be the ultimate cause(s) of the release. This thirst-independent regulation of vasopressin secretion is obviously of no importance in day to day control of water balance, but may help to maintain the arterial blood pressure in emergency situations.     

Inhibition of drinking in water-deprived rats by combined central angiotensin II and cholinergic receptor blockade.

The effect of blockade of central angiotensin II (AII) receptors and cholinergic receptors on thirst induced by water deprivation was studied in Sprague-Dawley rats and rats with hereditary hypothalamic diabetes insipidus (DI). Neither central AII nor cholinergic blockade alone affected drinking. Antagonism of both receptors simultaneously, however, significantly inhibited water intake of both Sprague-Dawley and DI rats. This inhibitory effect was not observed in water-deprived, nephrectomized rats. The combined antagonism on water intake was specific, since milk intake in hungry rats was not affected by simultaneous AII and cholinergic blockade. Isorenin concentrations in brain tissue were at control levels in water-deprived, nephrectomized, and non-nephrectomized Sprague-Dawley rats but were increased in water-deprived DI rats. The results suggest that angiotensin and cholinergic receptors in the brain have a physiological role in thirst. Thirst is maintained when either receptor is intact, but reduced when both receptors are inhibited by antagonists. They are independently capable of maintaining thirst.     

Vasopressin and angiotensin II receptors in rat aortic smooth muscle cells in culture

Rat aortic smooth muscle cells were isolated and maintained in primary culture. After 2-3 days, cells recovered their contractile phenotype and could be induced to contract in response to vasopressin and angiotensin II. Vasopressin- and angiotensin-specific binding sites were detected on these cells, using tritiated Lys8-vasopressin, Asn1-Val5-angiotensin II, and Sarc1-Ile8-angiotensin II. Vasopressin binding sites had Kd values of 30 and 12 nM for Lys8-and Arg8-vasopressin, respectively, and a maximal binding capacity of 25,000 sites/cell. They displayed several of the expected characteristics of vasopressin receptors involved in the vasopressor response in vivo. A highly significant correlation was found between the relative agonistic or antagonistic vasopressor potencies of a series of vasopressin structural analogues and their relative abilities to inhibit [3H]vasopressin binding to aortic smooth muscle cells. Specific binding sites for Asn1-Val5-angiotensin II and Sarc1-Ile8-angiotensin II had the following characteristics: Kd = 2.3 and 1.3 nM, respectively; maximal capacity: 50,000 sites/cell. Vasopressin and angiotensin did not modify the intracellular cyclic AMP content of aortic smooth muscle cells.     

Vasopressin release induced by hypothension is blunted in patients with diabetic autonomic neuropathy

The response of arginin-vasopressin (AVP) to baroreceptor activation (tilt testing) was investigated in patients with diabetic autonomic neuropathy (DAN). The present data show that hypothension induced by upright position showed a slight increase of AVP in patients with DAN in comparison with normal subjects and diabetic patients without DAN. These findings suggest that the blunted AVP response to hypothension may be due to lesions of afferent autonomic pathways present in DAN and plays a role in the pathogenesis of postural hypothension.     

Drinking induced by injections of angiotensin into forebrain and mid-brain sites of the monkey

1. Unilateral and bilateral injections of 1.0 mul. solutions of angiotensin II into specific brain sites produced copious drinking of water in the water-replete rhesus monkey (Macaca mulatta).2. Of six brain regions in seven monkeys into which a total of 368 microinjections of angiotensin II were made, three were sensitive to angiotensin II. In decreasing order of sensitivity, they were (i) a rostral zone that included the septum, the anterior hypothalamus and the preoptic region, (ii) a caudal zone consisting of the mesencephalic central grey, and (iii) the lateral and third ventricles near the foramen of Monro. Of the regions tested, those that were relatively inactive included (i) the mid line thalmus, (ii) the mid-brain reticular formation, and (iii) metencephalic points in the cerebellum, the 4th ventricle and the dorsal aspect of the pons.3. Bilateral microinjections of angiotensin II into the sensitive regions in doses as low as 0.75-6 ng were dipsogenic and, with increasing doses, drinking occurred in a dose-dependent fashion up to 500 ng, after which the amount drunk levelled off or was reduced. The dose-response curve for unilateral microinjections began at 12.5 ng, and at doses higher than 50 ng unilateral and bilateral microinjections were equipotent.4. The onset of drinking (without eating) averaged 2.1-3.2 min following the end of microinjections for all sensitive tissue sites. Injections into the ventricles produced significantly longer drinking latencies.5. Angiotensin I elicited drinking in amounts comparable to angiotensin II at a dose of 100 ng whereas analogues of angiotensin II were weak dipsogens. Of the three analogues tested, Phe(4), Tyr(8)-angiotensin II was the most potent dipsogen, followed by Ile(8)-angiotensin II. The 1-7 heptapeptide, des-Phe(8)-angiotensin II was an ineffective dipsogen. Carbachol microinjected into the most sensitive angiotensin drinking sites had no dipsogenic action in the water-replete monkey.6. Tachyphylaxis to angiotensin II was demonstrated as a reduction in mean water intake of 55 and 74 per cent on the second and third microinjections, respectively. This reduction appeared to be due to dilutional inhibition or signals from the amount of water ingested on the first microinjection of angiotensin II.7. Monkeys drank an amount equal to a normal daily intake following two to three microinjections of angiotensin II in doses of 100-250 ng into sensitive regions. This extra water load caused no reductions in normal daily water intake either for the remainder of the experimental day or 24 hr later.8. Pre-treatments with microinjections of an angiotensin-converting enzyme inhibitor, SQ 20,881, did not reduce the dipsogenic action of angiotensin I, suggesting that this and perhaps other peptide precursors act directly on receptor mechanisms to produce drinking. Attempts to change the polydipsic effects of angiotensin II were unsuccessful with pre-treatments of intracranial microinjections of either haloperidol, Ile(8)-angiotensin II or carbachol.9. Microinjections of angiotensin II dissolved in hypertonic saline solutions had no influence on water intake when compared with the same dose dissolved in distilled water or isotonic saline.10. Yawning was the only other response that appeared to be related directly to intracranial injections of angiotensin II. In some instances, a hyperactive state of the animal followed intraventricular injections of angiotensin II. In other instances, intracranial microinjections of angiotensin II were followed by quietude or e.e.g. and behavioural signs of light sleep.11. This work further confirms the findings of previous research which showed that angiotensin II is the most potent dipsogen in all species tested to date. This endogenous peptide appears to participate in natural thirst by acting on central mechanisms of extracellular thirst.     

Water deprivation-induced drinking in rats: role of angiotensin II

The role of angiotensin II in the control of water intake following deprivation of water for varying lengths of time was studied. Male rats were deprived of water for 0, 12, 24, 36, or 48 h. Water intakes were measured with and without pretreatment with the angiotensin I-converting enzyme inhibitor, captopril (50 mg/kg, ip). Captopril had no significant effect on water intake following either 0 or 12 h of water deprivation. However, captopril significantly attenuated water intake following 24-48 h of water deprivation with the magnitude of the attenuation increasing as the length of the period of water deprivation increased. Plasma renin activity was significantly increased over control levels after 24-48 h of water deprivation but not after 12 h of water deprivation. Plasma renin activity tended to increase as the length of the water-deprivation period increased. Serum osmolality and sodium concentration were significantly increased over control levels following 12-48 h of water deprivation. Serum osmolality and sodium concentration failed to show any further increases with increasing length of water deprivation beyond the increases following 12 h of water deprivation. The data indicate that the water intake of water-deprived rats can be divided into an angiotensin II-dependent component and angiotensin II-independent component. The angiotensin II-independent component appears to be more important in the early stages of water deprivation whereas the angiotensin II-dependent component becomes more important as the length of the water-deprivation period increases.     

Effect of intracerebroventricular deuterium oxide on water intake and AVP release induced by intravenous infusion of angiotensin II in sheep

The effect of intracerebroventricular (i.c.v.) infusion (0.02 ml min-1) of deuterium oxide (D2O), with NaCl added to isotonicity, on the water intake and arginine vasopressin (AVP) release caused by intravenous (i.v.) infusion of angiotensin II (AII) (4.8 nmol min-1) was studied in euhydrated sheep. The i.c.v. infusion of D2O, which started 80 min before commencement of the AII infusion, induced a water diuresis in four out of six animals and a measurable decrease in plasma AVP concentration. The i.v. infusion of AII effectively stimulated the AVP release and the response was unaffected by prior and simultaneous i.c.v. administration of D2O. However, the water intake measured 2 min after cessation of the AII administration was reduced by 50% when D2O was infused i.c.v. compared to that seen after simply the AII infusion. The inhibitory effect of D2O on AII-induced drinking disappeared rapidly after discontinuation of D2O administration. Compensatory increased drinking was seen during the first post-infusion hour, resulting in an equivalent cumulative intake of water at 60 min post-infusion in the two types of experiments. The present results support the idea that at least some of the cerebral effects of circulating AII on fluid balance are medicated via targets which are simultaneously accessible to influences from the blood and the cerebrospinal fluid.     

Contractions induced by angiotensin I, angiotensin II and bradykinin in isolated smooth muscle from the human detrusor.

In isolated human detrusor preparations angiotensin (At)II 10(-9)-10(-5) M caused concentration-dependent contractions. The contractile effect was immediate, and had an amplitude which at the highest concentration used, 10(-5) M, reached 103 +/- 16% of the mean contraction produced by K+ 124 mM (27.6 +/- 1.4 mN). The AtII effect was completely blocked by saralasin 10(-6) M, but was not affected by pre-treatment of the preparations with captopril or enalaprilate. There was a marked tachyphylaxis to the actions of the peptide. AtI (10(-8)-10(-5) M) also caused contractions which were rapidly developing, and subject to a marked tachyphylaxis. At a concentration of 10(-5) M, the mean amplitude was 66 +/- 9% of the K(+)-induced contraction. The contractions were blocked by saralasin 10(-6) M, but not by captopril or enalaprilate 10(-5) M. In contrast, contractions produced by AtI in rabbit mesenteric arteries were practically abolished by the angiotensin converting enzyme (ACE) inhibitors. The contractions induced by both AtI and AtII were practically abolished after pre-treatment in a nominally calcium-free Krebs solution. However, blockade of L-type calcium channels by nifedipine 10(-6) M reduced the responses to both AtI 10(-6) M (by 38 +/- 4%) and AtII 10(-6) M (by 39 +/- 7%), but never abolished the contractions. Bradykinin (Bk; 3 x 10(-8)-10(-5) M) had a contractile effect in detrusor preparations which varied widely between strips. At a concentration of 3 x 10(-6) M, a maximum was reached amounting to 30 +/- 10% of the K(+)-induced contraction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Circadian rhythms of activity and drinking in mice lacking angiotensin II 1A receptors.

Angiotensin II (ANG II) type 1 receptors are found in the mouse suprachiasmatic nucleus (SCN), the site of the circadian pacemaker, but their significance for circadian timekeeping is unknown. We examined circadian rhythms of wheel running and drinking in angiotensin AT(1a) receptor knockout (KO) mice. Mean daily running and drinking activity were elevated in KO mice under a light-dark (LD) cycle and in constant dark (DD). These increases were confined to the usual active (dark) period, thus, the 'amplitude' of running and drinking rhythms was higher in KO mice. The phase of entrainment to LD (measured by the onset of the daily active period) did not differ between groups, either in LD or on the first day of DD ('unmasked' phase). KO mice showed a modestly shorter free-running period (tau) in DD. The direction and magnitude of phase shifts to light pulses at two circadian times (CTs) in DD did not differ between groups. Core functions of the circadian system appear intact following AT(1a) receptor KO. The modestly shorter tau and increased rhythm amplitude in KO mice may be secondary to an effect of the mutation on the level of running and drinking activity.     

Impaired drinking to angiotensin II after subdiaphragmatic vagotomy in rats

Rats received total bilateral subdiaphragmatic vagotomy and, one month later, were fitted with chronic intravenous or intracerebroventricular cannulas. The vagotomized rats showed much reduced drinking compared with controls during intravenous infusion of angiotensin II. Their drinking to intracerebroventricularly administered angiotensin II was, however, less affected. The possible role of the vagus nerve in the mediation of angiotensin and other types of drinking is discussed.