Effects of peripheral administration of naloxone on beta-adrenergic mediated responses

A possible interaction between the opiate and beta-adrenergic systems in controlling body temperature, heart rate and water intake was investigated using adult male Sprague-Dawley rats. Peripheral administration of isoproterenol (8 and 50 micrograms/kg, s.c.) produced significant elevations of heart rate and tail skin and colonic temperatures, respectively. Peripheral pretreatment with naloxone (1 mg/kg, s.c.) was without effect on these beta-adrenergic responses. Administration of isoproterenol (25 micrograms/kg, s.c.) produced a significant increase in water intake which was abolished by peripheral pretreatment with naloxone (1 mg/kg, s.c.). Previous studies have suggested that the dipsogenic response to isoproterenol is mediated through angiotensin II. In the present study the angiotensin II-induced (200 micrograms/kg, s.c.) dipsogenic response was abolished by naloxone pretreatment. However, pretreatment with an equimolar dose of naloxone methobromide, an opiate antagonist which does not cross the blood-brain barrier, was ineffective in altering the dipsogenic response produced by peripheral administration of either angiotensin II or isoproterenol. Collectively, the data suggest that opiates do not alter peripheral beta-adrenergic responses and that the blocking effects of naloxone on the isoproterenol-induced drinking response is mediated centrally and may be due to blocking angiotensin II dipsogenesis.     

Peripheral conversion of L-5-Hydroxytryptophan to serotonin induces drinking in rats

Female rats administered serotonin (0.25 to 4.0 mg/kg, s.c.) showed a dose-dependent increase in water intake. The dipsogenic response was nearly maximal when 2 mg/kg was administered s.c. and plateaued by 2 hr after treatment. l-5Hydroxytryptophan (5-HTP), the precursor of serotonin, is also a potent dipsogen which induces drinking by way of the renin-angiotensin system. The possibility that the dipsogenic activity of 5-HTP is dependent on decarboxylation to serotonin was the objective of these studies. Either benserazide (30 mg/kg. s.c.), a central and peripheral decarboxylase inhibitor, or carbidopa (6.5 mg/kg, s.c.), a peripheral decarboxylase inhibitor, was administered 15 min prior to the dipsogen. Both decarboxylase inhibitors attenuated the dipsogenic response to 5-HTP (25 mg/kg, s.c.) but not to serotonin (2 mg/kg, s.c.). The peripheral serotonergic receptor antagonist, methysergide (3 mg/kg, i.p.), blocked the dipsogenic responses to both 5-HTP (25 mg/kg, s.c.) and serotonin (2 mg/kg, s.c.). There was no interaction between 5-HTP (18 mg/kg, s.c.) and serotonin (1 mg/kg, s.c.) when administered simultaneously with respect to their dipsogenic effects. Thus, the drinking response accompanying administration of 5-HTP occurs following peripheral conversion to serotonin which, in turn, activates peripheral serotonergic receptors. The mechanism(s) by which activation of peripheral serotonergic receptors increases water intake is not known, but appears to involve release of renin from the kidney.     

On the mechanism of serotonin-induced dipsogenesis in the rat

Subcutaneous administration of l-5-hydroxytryptophan (5-HTP), the precursor of serotonin, to female rats induces copious drinking accompanied by activation of the renin-angiotensin system. Neither a reduction in blood pressure nor body temperature accompanied administration of 5-HTP. The objective of the present study was to determine whether serotonin-induced dipsogenesis, like that of 5-HTP, is mediated via the renin-angiotensin system. Serotonin (2 mg/kg, SC)-induced drinking was inhibited by the dopaminergic antagonist, haloperidol (150 micrograms/kg, IP), which also inhibits angiotensin II-induced drinking. Both captopril (35 mg/kg, IP), an angiotensin converting enzyme inhibitor, and propranolol (6 mg/kg, IP), a beta-adrenergic antagonist, blocked serotonin-induced dipsogenesis. The alpha 2-adrenergic agonist, clonidine (6.25 micrograms/kg, SC), which suppresses renin release from the kidney, attenuated serotonin-induced water intake. The dipsogenic responses to submaximal concentrations of both serotonin (1 mg/kg, SC) and isoproterenol (8 micrograms/kg, SC) were additive rather than interactive suggesting that similar pathways mediate both responses. The serotonergic receptor antagonist, methysergide (3 mg/kg, IP), inhibited serotonin-induced drinking but had no effect on isoproterenol (25 micrograms/kg, SC)-induced dipsogenesis. However, neither serotonin (2 mg/kg, SC) nor isoproterenol (25 micrograms/kg, SC)-induced drinking was inhibited by cinanserin (25 micrograms/kg, IP). These data indicate that serotonin induces drinking in rats via the renin-angiotensin system. However, the results of the studies using methysergide suggest that serotonin appears to act at a point prior to activation of beta-adrenoceptors in the pathway leading to release of renin from the kidneys.     

L-5-hydroxytryptophan-induced drinking in rats: Possible mechanisms for induction

Administration of L-5-hydroxytryptophan (25 mg/kg body weight, SC) to female rats resulted in copious drinking. The dipsogenic response to administration of L-5-hydroxytryptophan (5-HTP) was blocked by propranolol (6 mg/kg body weight, IP), a β-adrenergic antagonist, and captopril (35 mg/kg body weight, IP), an angiotensin converting enzyme inhibitor. In addition, clonidine (12.5 and 25 μg/kg body weight, IP), a central α-adrenergic agonist known to inhibit renin release, attenuated drinking during 1, 2 and 3 hours after 5-HTP was administered. These results suggest that 5-HTP-induced drinking is mediated by way of the renin-angiotensin system. Haloperidol (150 μg/kg body weight, IP), a dopaminergic antagonist, also attenuated the dipsogenic response to administration of 5-HTP. In addition, incremental reductions in 5-HTP-induced drinking with increasing doses of spiperone (37.5 to 150 μg/kg body weight, IP), a more potent dopaminergic antagonist, were demonstrated. Thus, the dipsogenic response to administration of 5-HTP to rats is dependent on both the renin-angiotensin system and an intact dopaminergic pathway.     

Effect of beta-adrenergic antagonists on experimentally induced drinking in female rats

The nonspecific beta-adrenergic antagonist d,l propranolol, the specific beta 1-adrenergic antagonist atenolol, and the specific beta 2-adrenergic antagonist butoxamine were administered intraperitoneally (IP) to ovariectomized female rats in order to determine the role of beta-adrenergic receptors in drinking. D,l propranolol and atenolol administered at doses of 6, 12, and 18 mg/kg significantly attenuated the one-hour water intakes of rats administered angiotensin II (200 micrograms/kg, SC) and the water intakes of rats deprived of water for 24 hours. D propranolol, which has little beta-adrenergic blocking ability, administered at doses of 6 and 12 mg/kg, and butoxamine, administered at doses of 25 and 35 mg/kg, had no significant effects on the water intakes of angiotensin II treated or water deprived rats. Regardless of the dose, d,l propranolol, atenolol, and butoxamine failed to significantly alter the water intakes of rats administered 1.0 M NaCl (10 ml/kg, IP) The results provide evidence that beta 1-adrenergic receptors, but not beta 2-adrenergic receptors, are involved in mediating the increased water intakes induced by angiotensin II and water deprivation. On the other hand the increased water intake due to administration of hypertonic saline does not appear to mediated by beta-adrenergic receptors.     

Inhibition of angiotensin-induced water intake following hexamethonium pretreatment in the dog

The possibility that the pressor effects of angiotensin II influence angiotensin-induced thirst was investigated in dogs pretreated with hexamethonium. Ganglionic blockade reduced drinking elicited by i.c.v. administration of angiotensin II and totally eliminated drinking elicited by i.v. infusion of angiotensin II, whereas the pressor response to i.v. and i.c.v. angiotensin II was significantly increased. In contrast, hexamethonium had no effect on water intake or mean arterial blood pressure following i.c.v. isoproterenol, and produced a significant increase in drinking to s.c. isoproterenol, which was preceded by a large fall in mean arterial pressure. No changes in mean arterial pressure or drinking were observed during NaCl infusion in hexamethonium-pretreated animals. These results suggest that angiotensin II exerts its full dipsogenic activity only during normotensive or hypotensive states, and that the pressor effect of angiotensin II can antagonize its effects on water intake.     

Effect of pharmacological blockade on lithium-induced water drinking

Administration of lithium chloride (40 mg/kg i.p.) led to a significant increase in 24 h water intake of rats. Prior administration of propranolol and haloperidol blocked the effect of lithium while atropine failed to show such an effect. The dipsogenic effect of lithium is probably exerted through beta-adrenergic and dopaminergic pathways.     

The role of the renin-angiotensin system in compound 48/80-induced thirst in rats

The role of the renin-angiotensin system in compound 48/80 (3 mg/kg s.c.)-induced thirst in rats was investigated. Bilateral nephrectomy attenuated drinking induced by compound 48/80 but notpolyethylene glycol (PEG) (30%, 5 ml s.c.). Pretreatment with tripelennamine (histamine H1-receptor antagonist, 40 mg/kg i.p.) prior to the administration of compound 48/80 reduced the effect of compound 48/80 on drinking, but pretreatment with cimetidine (histamine H2-receptor antagonist, 40 mg/kg i.p.) or propranolol (β-adrenoceptor antagonist, 10 mg/kg i.p.) had no effect. The effect of SQ 14,225 (angiotensin converting enzyme inhibitor) in various concentrations (0.5–100 mg/kg s.c.) was investigated on the drinking response caused by compound 48/80 (3mg/kg s.c.), PEG (30%, 5 ml s.c.), isoprenaline (0.5 mg/kg s.c.) and hypertonic saline (5.8%, 2 ml s.c.). SQ 14,225 at a dose of 50 mg/kg significantly attenuated the compound 48/80-induced water intake when administered within 30 min prior to the injection of compound 48/80. Pretreatment with a high dose of SQ 14,255 (50 or 100 mg/kg s.c.) 15 min prior to the injection of dipsogens caused inhibition of the drinking response to compound 48/80 or isoprenaline, but not to PEG or hypertonic saline. Pretreatment with lower doses of SQ 14,225 (0.5 or 5 mg/kg, s.c.) had no inhibitory effect on compound 48/80- or isoprenaline-induced water intake. The inhibition of water intake by SQ 14,225 seems to be dependent on the dose and time between administration of SQ 14,225 and compound 48/80 or isoprenaline. Compound 48/80 and hypertonic saline were additively effective in producing the drinking response. The present results suggest that a decrease of plasma volume following plasma extravasation caused by s.c. administration of compound 48/80 may stimulate the juxtaglomerular cells of the kidney to release renin and that the consequent increase of angiotensin in turn stimulates water intake.It is concluded that the renin-angiotensin system makes a contribution to compound 48/80-induced thirst.     

Bethanechol-induced water intake in rats: possible mechanisms of induction

Acute administration of the parasympathomimetic agent, bethanechol, at 2, 4, 8 and 12 mg/kg body wt, IP, induced drinking and increased urine output of rats in a dose-dependent fashion. The first significant increases in both water intake and urine output above that of controls occurred when 4 mg/kg was administered. The drinking and increased urine output in response to administration of 8 mg bethanechol/kg was inhibited by atropine sulfate (3 and 6 mg/kg, IP). In addition, the beta-adrenergic antagonist, propranolol (6 mg/kg, IP, administered 30 min prior to treatment with bethanechol), inhibited bethanechol (8 mg/kg, IP)-induced drinking. Urine output, however, was unaffected by propranolol. Further, the angiotensin I converting enzyme inhibitor, captopril, inhibited significantly the drinking response, but not the increased urine output, accompanying administration of bethanechol (8 mg/kg). The effect of bethanechol and the beta-adrenergic agonist, isoproterenol (25 micrograms/kg) separately and in combination, on water intake was also studied. Both compounds increased water intake but they exerted no interactive effect when administered simultaneously. Administration of bethanechol (8 mg/kg) to conscious rats was also accompanied by a significant reduction in both mean blood pressure and heart rate that reached minimal levels within 10 min after treatment. Both responses had returned to control level by one hr after treatment. These results suggest that bethanechol induces drinking in rats by way of the renin-angiotensin system.     

Cerebral renin-angiotensin mediation of isoproterenol-induced thirst in the dog

Pretreatment of dogs with s.c. isoproterenol (10 micrograms/kg) caused a significant increase in drinking when 100 ng renin substrate was administered 3 min later to the lateral cerebral ventricles or subfornical organ. Isoproterenol itself was a potent peripheral (10 micrograms/kg), but unreliable central (0.01-1 microgram) dipsogen. The increased drinking after combined s.c. isoproterenol and intracerebroventricular (i.c.v.) renin substrate injections was significantly attenuated by i.c.v. captopril (20 micrograms), but was not influenced by s.c. captopril (500 micrograms/kg). However, combined i.c.v./s.c. pretreatment with captopril nearly abolished drinking to peripheral isoproterenol, or the combination of s.c. isoproterenol and i.c.v. renin substrate. Finally, single intracranial injections of the components of the renin-angiotensin system elicited dose-dependent and site-specific drinking. Renin substrate, angiotensin I and angiotensin III produced greater intakes at forebrain tissue sites than after i.c.v. or subfornical organ injections. Renin, on the other hand, was more potent i.c.v. than at forebrain loci. These results suggest that the cerebral renin-angiotensin system may participate in beta-adrenergic thirst mechanisms by increasing local angiotensin II biosynthesis in specific areas of the brain.     

Rapid desensitization of central beta-adrenoceptors in rat after subacute treatment with imipramine and calcium entry blockers.

The subcutaneous (s.c.) administration of isoprenaline to rats produced a dose-dependent increase in water drinking which was effectively antagonized by propranolol. This dipsogenic response was significantly inhibited after the intraperitoneal (i.p.) administration of imipramine (15 mg/kg/day), together with either of the following calcium entry blockers, for four days: diltiazem (15 mg/kg/day), verapamil (10 mg/kg/day), nifedipine (10 mg/kg/day) or nicardipine (15 mg/kg/day). Simultaneous injection of the inhibitor of the synthesis of serotonin, p-chlorophenylalanine (200 mg/kg/day, i.p.), did not affect this attenuation of the isoprenaline-induced response. Similarly, the selective 5-HT2 receptor agonist, 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) or the 5-HT2 receptor antagonist, ketanserin, had no significant effect on the attenuation of isoprenaline-induced drinking behaviour. The inhibition of isoprenaline-induced drinking, was, however, effectively attenuated after treatment of the animals with 6-hydroxydopamine (2.5 micrograms) or clonidine (30 micrograms), injected intracerebroventricularly (i.c.v.). These results indicate that the calcium entry blockers accelerate the desensitization of central beta-adrenoceptors possibly by an action on central adrenoceptors of the rat.     

A pharmacological analysis of the rat mast cell 5-HT gastric lesion test and the effects of ketanserin

Pronounced lesions of the gastric mucosa were induced by Compound 48/80 (1.0 mg/kg, i.v.) in rats protected from lethal shock of released histamine by the experimental histamine H₁-antagonist R 37 617. The intensity score of the lesions correlated with serum pepsinogen levels. Generally the stomachs were greatly distended and contained blood and regurgitated food residues. Compounds from many different pharmacological classes were tested in this procedure. Complete protection was obtained with serotonin antagonists. Also isoproterenol and salbutamol fully protected, apparently by counteracting the serotonin-induced circulatory stasis. No obvious effect was obtained with antagonists of acetylcholine, dopamine, and histamine, with α- and β-adrenergic blocking agents, with narcotic analgesics, and with various other agents unless doses were administered that by far exceeded the range of their primary activity. The lowest ED50 of ketanserin for protection was 0.15 mg/kg (time—2 hr, both s.c. and p.o.), indicating its high oral effectiveness against venoconstriction induced by endogenous serotonin. These doses also abolished cyanosis and reduced stomach distension, abnormal gastric contents, and serum pepsinogen levels. In view of the recently elucidated differences between serotonin antagonists, the mast cell 5-HT gastric lesion test appears appropriate to measure the peripheral serotonin S₂-antagonism of compounds.     

Effect of converting enzyme blockade on isoprenaline- and angiotensin I-induced drinking

1 Intravenous infusion of 0.072 mumol kg(-1) h(-1) (1Asp, 5-Ile) angiotensin I, 0.116 mumol kg(-1) h(-1) of (1-Asp beta-amid, 5-Val) angiotensin II or of (1-Asp, 5-Ile) angiotensin II, caused food-deprived and water-satiated rats to drink about 3.0 ml of water per animal. This indicates that angiotensin I has a 1.6 times stronger dipsogenic effect than the angiotensin II preparations when infused intravenously.2 The converting-enzyme-inhibitor SQ 20881 (Pyr-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro) (1.0 mg/kg i.v.) had no intrinsic dipsogenic effect.3 SQ 20881 given in combination with angiotensin I or angiotensin II potentiated the dipsogenic effect of angiotensin I, but not that of the two angiotensin II preparations.4 The drinking induced by isoprenaline (100 mug/kg, i.m.) was potentiated by SQ 20881 to the same extent as drinking produced by angiotensin I infusion.5 Angiotensin I plasma levels were determined after angiotensin I infusion and isoprenaline application. Both were significantly raised by SQ 20881.6 It is concluded that one of the mechanisms which mediate the dipsogenic effect of isoprenaline is stimulation of the renin-angiotensin system and that increased plasma levels of angiotensin I may play a substantial role in this type of drinking.     

Antagonism of the antinociceptive action of xylazine, an alpha-sympathomimetic agent, by adrenoceptor and cholinoceptor blocking agents

The potency of adrenoceptor and cholinoceptor agents to antagonize the antinociceptive action of xylazine, an α-sympathomimetic agent, was studied.Yohimbine (1–2 mg/kg) and piperoxan (2.5–10 mg/kg) antagonized very effectively the antinociceptive effects of xylazine in two tests: electrical stimulation of the rat's tail and the hot plate test in mice.2-Diethylaminomethyl-1,4-benzodioxane (883 F), dibozane, ethomoxane, tolazoline and dibenamine were much less effective in rats. Azapetine, moxisylyte and phenoxybenzamine were as ineffective as propranolol, but Kö 1366, a potent β-adrenoceptor blocking agent was effective in high doses. Prindolol, another potent β-adrenoceptor blocking agent, only decreased the effect of xylazine on the startle. Atropine and mecamylamine did not change the effect of xylazine in rats.On the hot plate test in mice, dibozane, ethomoxane, tolazoline, phentolamine, dibenamine, chlorpromazine, clomipramine, pindolol, Kö 1366, atropine and atropine methyl nitrate were very effective in antagonizing the effect of xylazine, when both drugs were given intraperitoneally, but were less active when xylazine was given intracerebroventricularly. When the potential antagonist and xylazine were both administered into the cerebral ventricle of the brain, only piperoxan, yohimbine, tolazoline, clomipramine, Kö 1366, atropine and atropine methyl nitrate were effective. Phenoxybenzamine, azapetine, moxisylyte, propranolol and mecamylamine were ineffective by all routes of administration.These results suggest the involvement of receptors with properties in common with classical α-adrenoceptors in the antinociceptive action of xylazine, but these receptors seem to be distinct. In addition, in the hot plate test central cholinergic mechanisms could be involved as well as peripheral mechanisms.     

Dissociation of dipsogenic and depressor responses produced by hypotensive agents

Since the direct, vascular, smooth-muscle-relaxing agents isoproterenol and diazoxide produce substantial drinking responses in water-satiated rats, other direct-acting (sodium nitrite, sodium nitroprusside, hydralazine) and indirect (methyldopate) hypotensive drugs were administered to assess their dipsogenic efficacy. Although characteristic hypotensive dose-effect relations were observed for these drugs, no significant drinking occurred over the range of doses producing hypotension. Combinations of the three direct-acting agents with the alpha-adrenergic blocker tolazoline yielded moderate dipsogenic effects, although totazoline alone was dipsogenically ineffective at these doses (1 and 10 mg/kg) as determined in a previous study. Thus, the ineffectiveness of the direct-acting agents as dipsogens was not due to inherent behavioral toxicity. Propranolol, which was shown previously to antagonize diazoxide-induced drinking did not antagonize the hypotensive effect of diazoxide. Since some of the drugs used increase plasma renin activity, but failed here to stimulate drinking, increased plasma renin activity may be an incomplete explanation of the dipsogenic activity of certain peripherally-acting agents.     

Effects of systemic and intracranial inhibition of angiotensin-converting enzyme on isoproterenol-induced drinking in the rat

We have investigated the effects of separate and combined s.c. and intracerebroventricular (i.c.v.) injections of captopril, an inhibitor of angiotensin I-converting enzyme, on isoproterenol-induced thirst. Whereas s.c. injections of captopril (0.5 mg/kg) increased drinking, combined s.c. and i.c.v. (20 μg) injections of captopril nearly abolished drinking to isoproterenol (0.1 mg/kg s.c.). This inhibition was not caused by general debility of the rats since the same treatment did not reduce drinking to 12 h water deprivation. Intracerebroventricular injection of 20 μg captopril alone also greatly reduced isoproterenol-induced drinking, perhaps because it leaked into the circulation; captopril i.c.v. also reduced the pressor response to i.v. injection of hog renin (0.1 Gold blattUnit) by about 65%. These results support the hypothesis that the renin-angiotensin system participates in the stimulation of drinking by isoproterenol and that the enhancement of drinking caused by inhibition of CE only in the circulation is the result of increased synthesis of angiotensin II in the brain.     

Effect of acute administration of bromocriptine on isoproterenol- and angiotensin II-induced water intake in estrogen-treated rats

Chronic administration of an estrogenic agent is well known to attenuate the drinking response of rats to treatment with a variety of dipsogenic agents, and to increase plasma concentration of prolactin. Treatment with prolactin is also known to reduce the drinking response to administration of the dipsogenic agent, isoproterenol. Hence, a possibility existed that the antidipsogenic effect of chronic treatment with estrogen was mediated by an increased plasma prolactin concentration. Since bromocriptine, a dopaminergic agonist, is known to reduce plasma prolactin concentration in estrogen-treated rats, it was administered (1.0 mg/kg, IP) 15 min prior to treatment with either isoproterenol (25 micrograms/kg, SC) or angiotensin II (200 micrograms/kg, SC). The results suggest that the antidipsogenic effect of chronic treatment of rats with estradiol benzoate (30.4 and 45.7 micrograms/kg/day) can be reversed, at least partially, by acute administration of bromocriptine.     

The cardioselectivity of β-adrenergic blocking agents revealed by interaction with salbutamol and isoproterenol in the KCN test in rats

The interaction of seven β-adrenergic blocking agents with salbutamol and isoproterenol was studied in the potassium cyanide test in rats. Salbutamol was used at a dose that provided protection from KCN lethality and isoproterenol at an overdose that failed to protect, presumably because of latent cardiotoxicity. Salbutamol-induced protection was abolished at the following doses (s.c., mg/kg): timolol (0.0085), bunolol (0.010), propranolol (0.038), pindolol (0.15), metoprolol (3.93), atenolol (5.69), and practolol (> 10.0). Survival was restored dose-dependently in isoproterenol-overdosed rats only by atenolol (0.44), practolol (0.51) and metoprolol (1.06). The cardioselectivity ratio (i.e., salbutamol antagonism/isoproterenol antagonism) for these three compounds was as follows: practolol (> 19.6), atenolol (12.9), and metoprolol (3.82). The described interaction tests appear to provide experimental data that are useful for the evaluation of cardioselective β-adrenergic blockade.     

Time-related facilitation and suppression of drinking by muscarinic anticholinergic drugs in water non-deprived rats

Effects of tertiary anticholinergic drugs, atropine (1.3, 2.5, 5 and 10 mg/kg, s.c.) and scopolamine (0.13, 0.25, 0.5 and 1 mg/kg, s.c.), and a quaternary anticholinergic drug, methylatropine (1.3, 2.5, 5 and 10 mg/kg, s.c.), on the drinking behavior were investigated in water non-deprived rats that were housed in a 12-hr light-dark situation (light period: 6:00-18:00) with a free access to food. Atropine, 5 mg/kg, and scopolamine, 0.13 and 0.25 mg/kg, administered at 12:00, significantly increased the drinking during the 12:00-18:00 period. Furthermore, lower to medium doses of atropine increased the drinking during the 18:00-6:00 period. In contrast, the drinking did not change during the 12:00-18:00 period, but decreased during the 18:00-6:00 period in a dose-dependent manner after administration of methylatropine at 12:00, whereas the drinking during the 18:00-24:00 period decreased in a dose-dependent manner when both the tertiary and quaternary drugs were administered at 18:00. However, the drinking during the 24:00-6:00 period increased in the rats that were administered atropine at the dose of 5 or 10 mg/kg at 18:00, while the drinking still decreased after methylatropine at the same time. The present results suggest that in water non-deprived rats, central muscarinic cholinergic blockade is effective for both increasing and decreasing drinking behavior, depending on the doses, when the drug is administered, and time span between the drug administration and the behavior observation. It is also suggested that peripheral cholinergic blockade monotonously suppresses the drinking behavior.     

Effect of an angiotensin converting enzyme inhibitor (SQ 14,225) on beta-adrenergic and angiotensin-induced thirsts.

The effect of acute administration of SQ 14,225, a new angiotensin converting enzyme inhibitor, on the drinking response of female rats administered either isoprenaline, angiotensin I, or angiotensin II was studied during 2 h after treatment. Administration of isoprenaline (25 micrograms/kg body wt) was accompanied by a significant increase in water intake when compared with saline-treated controls. Acute administration of a constant dose of isoprenaline (25 micrograms/kg body wt) and increasing doses of SQ 14,225 (5--50 mg/kg) was accompanied by a dose-related, linear decrease in water intake. Acute administration of either angiotensin I or angiotensin II (200 micrograms/kg body wt) was accompanied by a significant increase in water intake. The dipsogenic response to angiotensin II was not affected by acute administration of 35 mg SQ 14,225/kg body wt. However, at the same dose of SQ 14,225, angiotensin I-induced thirst was attenuated. Since isoprenaline-induced and angiotensin I-induced, but not angiotensin II-induced, thirsts are blocked by SQ 14,225, the results suggest that isoprenaline-induced thirst is mediated by way of the renin--angiotensin system.