The overall goal of this proposal is to gain a better understanding of how the brain integrates the information it receives from the arterial baroreceptors. Such understanding provides insights into how the central nervous system regulates blood pressure and heart rate under normal and pathological situations. During the tenure of this award we have shown that the physiological and pharmacological mechanisms responsible for the integration of baroreceptor afferent inputs are altered in chronically hypertensive animals. The specific goal of this competitive renewal is to further define the nature, the time course and the functional significance of these alterations. To this end, experiments have been designed to test the general hypothesis that the central resetting of the arterial baroreflex observed in chronic renal wrap hypertension is mediated, at least in part, by inhibition of transmission within the NTS. Previous work during the tenure of this award has provided insights into specific alterations that occur in hypertension; therefore 4 specific aims are proposed to test hypotheses that arise from these studies.
Specific Aim 1 : Chronic hypertension is associated with increased GABAA mediated inhibition within the NTS. This inhibition is the result of an increase in the discharge of GABAergic neurons in the NTS. These GABAergic neurons inhibit other NTS neurons that integrate baroreceptor afferent inputs; therefore these changes contribute to a blunting of NTS neuronal responses and reflex resetting.
Specific Aim 2 : Chronic hypertension induces increased post-synaptic expression of GABAB receptors in NTS neurons receiving monosynaptic aortic nerve inputs. This increase in GABAB receptor function contributes to a blunting of NTS neuronal responses and reflex resetting in chronic hypertension.
Specific Aim 3 : Alterations in GABAA and GABAB mechanisms within the NTS of chronically hypertensive rats result from a tonically elevated level of peripheral afferent input from the arterial baroreceptors and cardiopulmonary mechanoreceptors.
Specific Aim 4 : In chronically hypertensive rats the number of NTS neurons active at the resting level of arterial pressure and the number of neurons activated in response to graded increases in pressure is increased compared to the number of neurons active and activated in normotensive rats. The level of baroreceptor afferent input to the NTS is increased in hypertension. It is hypothesized that during chronic hypertension alterations occur in the physiology and pharmacology of NTS neurons that result in enhanced inhibition and counteract the elevated afferent input. This normalizes NTS neuronal discharge and thereby reflex gain. These adaptations confer a baroreflex buffering capability that might otherwise be greatly reduced in hypertension. Therefore, understanding the mechanisms that induce and underlie these adaptations will be of great importance in our understanding of cardiovascular regulation in hypertension.
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