Rose M. Threatte

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.

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/lg was administered s.c. and plateaued by 2 hr after treatment. l-5-Hydroxytryptophan (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 mechanisms(s) by which activation of peripheral serotonergic receptors increases water intake is not known, but appears to involve release of renin from the kidney.

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 beta-adrenergic antagonist, and captopril (35 mg/kg body weight, IP), an angiotensin converting enzyme inhibitor. In addition, clonidine (12.5 and 25 microgram/kg body weight, IP), a central alpha-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 microgram/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 microgram/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.

Effects of serotonin and L-5-hydroxytryptophan on plasma renin activity in rats ☆

The effects of dipsogenic doses of l-5-hydroxytryptophan (5-HTP) and serotonin on plasma renin activity (PRA), blood pressure, and body temperature were determined in unanesthetized female rats. Both serotonin (2 mg/kg, s.c.) and 5-HTP (25 mg/kg, s.c.) induced six-fold increases in PRA measured 1 hr after drug administration. The central and peripheral decarboxylase inhibitor, benserazide (30 mg/kg, s.c.), as well as the peripheral decarboxylase inhibitor, carbidopa (6.5 mg/kg s.c.), prevented the increase in PRA associated with administration of 5-HTP. This suggests that 5-HTP must be converted to serotonin peripherally to increase PRA. At the doses used, serotonin decreased mean blood pressure and colonic temperature of unanesthetized rats while 5-HTP was without effect. The increase in PRA induced by 5-HTP does not appear, therefore, to be a response to either hypotension or a decrease in colonic temperature. Since 5-HTP must be converted to serotonin to initiate both a drinking response and an increase in PRA, the results suggest that the decrease in blood pressure and colonic temperature following administration of serotonin may not be important in induction of the drinking response and the increase in PRA. The mechanism by which activation of the renin-angiotensin system occurs following peripheral administration of either 5-HTP or serotonin remains for further study.

Response to Thermal Stress in the Rat following Acute Administration of Ethanol

Several thermoregulatory responses (i.e., colonic temperature, tail-skin temperature, rate of oxygen consumption) were measured in the rat following acute administration of either saline or 3 g ethanol/kg BW i.p. at ambient temperatures (Ta) of 17, 25, and 32 degrees C. The magnitude of the ethanol-induced, hypothermic response was inversely related to Ta, with the decrease in colonic temperature (Tco) at 120 min postinjection ranging from 0.1 degree C at Ta 32 degrees C to 3.2 degrees C at Ta 17 degrees C. Depression of rate of oxygen consumption (heat production) was a major factor contributing to ethanol-induced hypothermia, with no observed differences in heat loss as assessed by differences in the responses of tail skin temperature. Thermoregulatory responses were also measured following acute administration of ethanol at Ta 25 degrees C and immediate exposure to either Ta 32 or 17 degrees C. The increase in Tco of ethanol-treated rats was delayed compared to controls following exposure to 32 degrees C. In addition, tail skin temperature and rate of oxygen consumption of treated rats were significantly lower. The delayed rise in Tco is most likely the result of a reduction in rate of oxygen consumption. When administered ethanol at Ta 25 degrees C and then exposed to Ta 17 degrees C, the rats exhibited a significant recovery from the metabolic depression that characterized the administration of ethanol during exposure to Ta 17 degrees C. This was most likely related to differences in the clearance of ethanol from blood. The results of this study are consistent with the suggestion that the physiologically significant inhibitory effect of acute administration of 3 g ethanol/kg BW on thermoregulatory responses of rats is manifested at the level of heat production rather than heat loss and that the effect is exacerbated by a reduction in Ta.

Dipsogenic effect of L-5-hydroxytryptophan in rats ☆

The precursor of serotonin, l-hydroxytryptophan (5HTP), is a potent dipsogen in the rat. Peripheral administration of increasing doses of this compound increased water intake in a dose-dependent fashion. Peripheral administration of other analogs of tryptophan, including d-tryptophan, l-tryptophan and acetyltryptophan, failed to affect water intake at a dose at which 5HTP induced maximal drinking (25 mg/kg, SC). The dipsogenic effect of melatonin, one of the metabolites of serotonin, was also tested. At any of 6 different doses (0.5 to 50 mg/kg, SC), melatonin failed to affect water intake in the rat. The mechanism by which 5HTP induces drinking is not known with certainty but could involve its conversion to serotonin, a known dipsogenic agent.

DEPENDENCE OF β-ADRENERGIC RESPONSIVENESS ON THYROID STATE OF MALE RATS

1 The dose of thyroxine (0‐150 μg/kg body weight) administered subcutaneously daily to surgically thyroidectomized male rats was correlated significantly with their metabolic activity as assessed by rate of oxygen consumption and colonic temperature.

Effect of acute administration of isoproterenol and angiotensin II, separately and in combination, on water intake and blood pressure of rats.

The effects of administration of isoproterenol, a beta-adrenergic agonist, and angiotensin II, a peptide, separately and in combination, on water intake and blood pressure of rats were studied. The results of 6 factorially designed studies in which 4 different doses of each compound were administered revealed that water intakes increased directly with the logarithm of increasing doses of each. The effect of simultaneous administration of the 2 compounds on water intake was additive at submaximal doses of each. No interactive effects on water intake were observed when the 2 compounds were administered simultaneously in any study. Reduction in urine output appears to be a more sensitive response to administration of isoproterenol than increase in water intake since it was virtually abolished at a dose (2.5 micrograms/kg SC) that had no effect on water intake. The lowest doses of angiotensin II (25 and 50 micrograms/kg SC) had no significant effect on either water intake or urine output. The effect of simultaneous administration of both compounds on urine output was essentially the same as that accompanying administration of isoproterenol alone. Following administration of angiotensin II (150 micrograms/kg, SC) mean systemic blood pressure of unanesthetized, chronically cannulated rats reached maximal levels within 5 min and returned to pretreatment control level by 60 min. Following administration of isoproterenol (25 micrograms/kg, SC), mean systemic blood pressure decreased within 5 min, was maximally depressed by 30 min and had returned halfway to the pretreatment control level by 60 min. Simultaneous administration of isoproterenol and angiotensin II failed to induce a significant change in blood pressure. These results are of particular interest since they show that neither the pressor effect of angiotensin II nor the depressor effect of isoproterenol is essential for the induction of drinking by these 2 compounds.

Renal-thyroid interrelationship in normotensive and hypertensive rats☆

An increase in the weight of the thyroid gland, accompanied by reductions in uptake and release of 1311, serum T3 and reverse T3 concentrations and an increase in serum TSH concentration, occurs during the development of renal hypertension in rats. Renal function, as assessed by BUN, serum and urinary creatinine concentrations, and ability to concentrate urine during dehydration, is depressed. The kidneys of both normotensive and renal hypertensive rats contain a thyroid depressing factor (TDF) which inhibits uptake of 131I both in vivo and in vitro as well as inhibiting the lactoperoxidase enzyme in vitro. The kidneys of renal hypertensive rats contain less, and the serum more, TDF than those of normotensive rats. Whether TDF is produced as a result of hypertension per se or as a result of renal damage accompanying hypertension remains for further study. TDF appears to be a peptide with a molecular weight in the range of 400 to 419 daltons.

Normal excretion of m-hydroxymandelic acid in hypertensive patients

o-Hydroxymandelic acid (OHMA), m-hydroxymandelic acid (MHMA) and p-hydroxymandelic acid (PHMA) were measured in the urine of 42 normotensive and 54 hypertensive patients. Patients having high urinary MHMA levels were all found to be ingesting medications containing m-synephrine (phenylephrine). These patients also had high levels of urinary m-synephrine which was excreted as the glucuronide. When patients ingesting m-synephrine were excluded from the analysis, no significant differences were observed between the two groups for the urinary excretion of OHMA, MHMA and PHMA.