Previous work in this laboratory has shown that GABA blocks the osmotic stimulation of vasopressin release. The hypothesis that will be tested in this proposal is that GABA or the pharmacological activation of the endogenous forebrain GABAergic system is capable of interfering with both osmotic and baroreceptor stimulated vasopressin release mechanisms. A corollary hypothesis that will be examined is that GABA asserts a tonic inhibition on the vasopressin system as part of the baroreflex pathway. During osmotic and baroreceptor activated vasopressin release, vasopressin levels and changes in arterial pressure, heart rate, cardiac output and total peripheral resistance will be monitored. To limit the distribution of centrally administered GABA to the forebrain, a cold cream plug will be placed in the posterior third ventricle. The first study will examine GABA interactions with osmotic stimuli. Acutely anephric rats will be infused with hypertonic sodium chloride to stimulate osmotic activated vasopressin release. In the second study, baroreceptor mediated vasopressin release will be stimulated with sequential administration of captopril (a renin-angiotensin system antagonist) and a ganglionic blocking agent (a sympathetic nervous system antagonist) to lower arterial pressure. In both of these studies, GABA, an uptake inhibitor of GABA (nipecotic acid), or a metabolism inhibitor of GABA (Gamma-vinyl GABA) will be given to assess the effect on plasma vasopressin levels and systemic hemodynamics. The third study will focus on the role of GABA in the tonic inhibition of vasopressin release through a baroreflex mechanism. Local injections of the GABA antagonist, bicuculline, into the supraoptic nucleus, will be used to investigate this action. These studies will contribute significantly to an understanding of the role of the GABAergic system in modulating vasopressin release.
