The central nervous system plays a key role in the regulation of the cardiovascular system and altered central neural control of blood pressure (BP) may participate in the initiation or maintenance of hypertension. Three brainstem areas are of key importance in BP regulation: the rostral ventrolateral medulla (RVL), the caudal ventrolateral medulla (CVL), and the nucleus tractus solitarius (NTS). Recent data from pharmacological studies indicate that tonically active GABAergic synapses in each of these regions influence BP. The goal of the experiments described in this proposal is to study the role of GABAergic neurotransmission in the NTS, RVL, and CVL in the regulation of BP and to determine whether altered GABAergic neurotransmission in these regions may be involved in the pathogenesis of hypertension. The first set to experiments will utilize a pharmacological approach to study how drugs which influence GABAergic neurotransmission affect blood pressure and heart rate when administered directly into the NTS, RVL, or CVL. These studies will focus primarily on the effects of indirect-acting GABA agonists, since the responses to such drugs should reflect the ongoing level of GABAergic neurotransmission. Responses to these drugs will be compared in hypertensive and normotensive rats. The second set of studies will use a neurochemical approach to examine similar questions. In these studies, the rate of GABA synthesis (which presumably reflects the rate of GABA released into the synapse) will be determined by measuring the accumulation of GABA following local inhibition of its metabolism. A push-pull perfusion technique will be used to confirm that observed changes in synthesis do reflect changes in GABA release. Using these techniques, it will be determined whether changes in cardiovascular afferent activity affect GABAergic neurotransmission in the NTS, RVL, or CVL. These techniques will also be applied to determine whether GABAergic neurotransmission is altered in the NTS, RVL, or CVL in experimental hypertension in rats. These studies will provide a comprehensive analysis of GABAergic neurotransmission in the NTS, RVL, and CVL as related to the regulation of blood pressure and the pathogenesis of hypertension. It is expected that these studies will provide new and important information on the role of the brain in hypertension, and may therefore offer new insights into the treatment or prevention of hypertension.
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