The goal of the current proposal is to elucidate the role of atrial natriuretic peptide (ANP) in the pathogenesis of NaCl sensitive hypertension in a rodent model, the NaCl sensitive spontaneously hypertensive rat (SHR-S). The hypothesis of the proposal is that ANP in both the peripheral circulation and the brain plays a role in the pathogenesis of hypertension in SHR-S. Previous findings that SHR-S fail to increase circulating ANP levels appropriately compared to WKY in response to dietary NaCl supplementation and that replacement of the deficiency in circulating ANP levels in SHR-S by infusion of exogenous ANP prevents the NaCl sensitive component of hypertension suggest that NaCl sensitive hypertension is an ANP deficient state and that circulating, ANP protects against the NaCl induced exacerbation of hypertension in the SHR-S.
Specific Aim 1 will test the hypothesis that ANP gene expression, receptor mechanisms and metabolic clearance are altered in SHR-S compared to NaCl resistant hypertensive (SHR-R) and normotensive (WKY) controls.
Specific Aim 2 will test the hypothesis that circulating ANP protects against the development of NaCl sensitive hypertension in SHR-S by determining the effects of reducing endogenous plasma ANP levels by chronic administration of a monoclonal antibody to ANP and of increasing endogenous ANP levels by chronic administration of a neutral endopeptidase inhibitor on the development of hypertension in SHR-S, SHR-R and WKY maintained on high NaCl and basal NaCl diets.
Specific Aim 3 will utilize push-pull microperfusion, microinjection and chronic microinfusion techniques to test directly the hypotheses that endogenous ANP acts as an inhibitory neuromodulator of NE release in AHA and that this effect contributes to increased sympathetic nervous system activity and NaCl sensitive hypertension in SHR-S. Exaggerated pressor responses to microinjection of monoclonal antibody to ANP into the nucleus tractus solitarii (NTS) have been found in SHR-S compared to SKY, suggesting that endogenous ANP in NTS plays a role in blood pressure control in SHR-S.
Specific Aim 4 will test the hypothesis that endogenous ANP acts at the level of NTS to lower blood pressure and to modulate arterial baroreflex sensitivity. The effect of altering endogenous ANP levels in NTS by microinjecting a monoclonal antibody to ANP and a neutral endopeptidase inhibitor and/or C-ANP(4-23) on blood pressure, heart rate, sympathetic outflow and sensitivity of arterial baroreflex mediated control of heart rate and lumbar and splanchnic sympathetic nerve activity will be observed. These studies will enhance our understanding of the role of brain and cardiac (circulating) ANP in the pathogenesis of NaCl sensitive and resistant forms of spontaneous hypertension in the rat and in the adaptation of normotensive rats to high dietary NaCl intake. This proposal will lay the groundwork for development of ANP potentiation as an interesting new approach to the treatment of essential hypertension, particularly NaCl sensitive hypertension in man.
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