John Kucharczyk

Central mechanisms for apomorphine-induced emesis in the dog.

In order to investigate whether different receptor populations mediate emesis induced by intracerebroventricular (i.c.v.) and intravenous (i.v.) apomorphine, adult beagle dogs were tested with various doses of the drug with and without central and peripheral pretreatment with the dopamine antagonist sulpiride. The threshold dose of apomorphine to induce emesis by i.c.v. injections was 30-50 times lower than via the i.v. route, while the response latencies after i.c.v. administration were typically longer and the number of bouts of vomiting greater. I.v. pretreatment with sulpiride was more effective than i.c.v. pretreatment in blocking emesis induced by i.v. apomorphine, whereas both i.v. and i.c.v. sulpiride effectively blocked vomiting after i.c.v. apomorphine. Finally, in separate experiments, surgical interruption of blood flow in the region of the area postrema permanently abolished the emetic response to i.c.v. apomorphine, but only transiently disrupted emesis induced by i.v. apomorphine. These data suggest the possibility that i.v. and i.c.v. apomorphine-induced emesis may be mediated by separate dopamine receptors on the cerebrospinal fluid-side and blood-side of the area postrema.

Emetic effects of centrally administered angiotensin II, arginine vasopressin and neurotensin in the dog

Short-latency emetic responses were induced in dogs by injecting angiotensin II (AII), arginine vasopressin (AVP), and neurotensin (NTN) into cerebroventricular (ICV) and cisternal (ICT) sites also responsive to the emetic effects of apomorphine (APO). Angiotensin III, bradykinin, bombesin, oxytocin, adrenocorticotropic hormone, substance P, gastrin-related peptide and cholecystokinin were ineffective. The results suggest a possible dopaminergic mediation of peptide-induced emesis by receptors in the area postrema (AP).

Drinking behavior following electrical stimulation of the subfornical organ in the rat

Electrical stimulation of the subfornical organ (SFO) through implanted stainless-steel electrodes produced drinking in water-sated rats. Drinking was elicited primarily during the interstimulation (OFF) periods. Water intake in rats with hippocampal electrode placements occurred during both ON and OFF periods at current intensities (24-100 microA) similar to rats with SFO placements. These findings support the hypothesis that the SFO is involved in the central control of fluid balance.

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.

Neuroendocrine mechanisms mediating fluid intake during the estrous cycle

Gonadal steroids appear to influence fluid-electrolyte homeostasis through behavioral as well as renal mechanisms. The marked fluctuations in drinking behavior observed during the estrous cycle of the female rat may be due to an interaction between estrogen and the dipsogenic peptide hormone, angiotensin II, at the level of basal forebrain receptors. The preoptic region in particular may play an important integrative role in the maintenance of extracellular fluid balance in synchrony with the estrous cycle, since it contains receptors for angiotensin and estrogen. Prolactin may also directly participate in mechanisms of extracellular thirst, while an exact role for vasopressin has yet to be established. Recent studies also suggest that estrogens may influence body fluid regulation by interacting with several neurotransmitters, including serotonin, dopamine and noradrenaline.

Central angiotensin-induced water intake and salt appetite in the pig

Single intracranial injections of the peptide analogues of angiotensin and the enzyme renin induced drinking of water and 1.8% NaCl solution in prepubertal female pigs maintained ad libitum on a sodium-free diet with unrestricted access to both fluids. Over the dose range 10(-12)-10(-9) mol angiotensin (AI), angiotensin II (AII), angiotensin III (AIII), and renin substrate (RS), the volumes of water and salt solution ingested were dose-dependent. As in other vertebrates, AII was the most potent and rapidly acting dipsogen. However, unlike in the rat, dog and pigeon, AIII was highly effective in stimulating both water intake and salt appetite, whereas AI and RS were relatively weak. Pretreatment of intracranial sites with 10(-9) mol of the AII competitive antagonist, Sar1-Ala8-angiotensin, had no effect on the volume of water or 1.8% NaCl ingested after 10(-10) mol AIII, suggesting that in the pig AIII can exert its dipsogenic effects without acting on central AII receptors. Single microinjections of 1 and 10 mU of renin also elicited dose-dependent drinking of water and 1.8% NaCl, but compared with the peptide analogues of angiotensin the responses had a longer latency and duration and were more variable between individual animals.

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.

Altered drinking responses in dogs with chronic metabolic alkalosis.

Chronic chloride depletion alkalosis in dogs causes a lowered osmotic threshold and increased sensitivity for vasopressin (AVP) release. Since AVP release and drinking behavior normally are closely associated over a narrow range of changes in plasma osmolality (Posm), we investigated whether alkalotic dogs would also show an altered responsiveness to the dipsogenic effects of angiotensin II (ANG II) and osmotic stimuli. Dogs made chronically alkalotic by a combination of chloride-free diet and furosemide injections developed polydipsia in the absence of any increase in solute intake and in the presence of a significant reduction in Posm. The animals were chronically hypochloremic, hyponatremic and hypokalemic, and appeared to be extracellular fluid (ECF) contracted. Plasma renin activity (PRA) was 10-fold higher in alkalotic dogs than controls. When Posm was increased by a slow 2 hr infusion of hypertonic sodium sulfate, alkalotic dogs were found to have a significantly lower osmotic threshold for inducing drinking (289.8 +/- 1.1 mOsm/kg/H2O vs. 305.1 +/- 1.3 mOsm/kg/H2O in controls), but the slope or sensitivity of the water intake/Posm relationship was not significantly different. Finally, compared to normal animals, alkalotic dogs were unresponsive to the dipsogenic effects of IV ANG II. These data indicate that the central mechanisms which mediate drinking in response to cellular and extracellular thirst stimuli are altered in chronic metabolic alkalosis.