Although the contribution of high dietary NaCl intake to hypertension has been recognized for over 5 decades, the mechanism(s) by which NaCl elevates blood pressure (BP) remains enigmatic. Evidences from our laboratory and from others suggests that the central and peripheral noradreneric (NA) systems play important roles in the NaCl induced rise in BP in genetically predisposed individuals.
The aim of this proposal is to test the hypothesis that increase dietary NaCl elevates BP by reducing noradrenergic activation of sympathoinhibitory neurons in the anterior hypothalamic area (AHA). Two rat models of hypertension will be employed: (1) the NaCl sensitive spontaneously hypertensive rat of the Okamoto strain (SHR-S), in which hypotension is exacerbated by NaCl loading, and (2) the Dahl salt sensitive (S) rat, in which the development of hypertension is completely dependent on NaCl loading. Biochemical methods will be employed to test the hypothesis that, in NaCl sensitive SHR-S and Dahl-S rats, dietary NaCl loading causes decreases in NA input to AHA, that are temporally related to the NaCl induced rise in BP. Electrolytic and chemical lesions of the AHA will be employed to assess the contribution of AHA neurons to BP homeostasis in NaCl loaded animals, specifically, to test the hypothesis that the NA input to the AHA is attenuated and has a blunted sympathoinhibitory effect in NaCl loaded SHR-S and Dahl-S rats. In vitro and in vivo methods will be employed in order to test the hypothesis that release of NA into the AHA is depressed in NaCl loaded SHR-S and Dahl-S rats. Using these techniques, we will further test the hypothesis that alpha 2 mediated presynaptic inhibition of NA release from AHA terminals is increased in SHR-S and Dahl-S on high NaCl diets. The final study will extend these findings by testing the hypothesis that AHA neurons in NaCl loaded SHR-S and Dahl-S rats have intact intrinsic sympathoinhibitory control ability, but the decreased NA excitation of these neurons results, at least in part, in increased sympathetic tone and increased BP following NaCl loading. In a final experiments, we will attempt to attenuate or abolish NaC1 exacerbated hypertension in the SHR-S by chronically elevating the level of NA in the AHA. These studies will elucidate the sympathoinhibitory role of NA inputs to AHA in normotensive and NaCl resistant hypertensive (SHR-R and Dahl-R) rats and will define the abnormality in this pathway that underlies NaCl sensitive hypertension in genetically predisposed individuals.
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