Many forms of hypertension are exacerbated by increased dietary salt (salt-dependent hypertension) but the mechanisms are unknown. The overall objective of this proposal is to investigate the autonomic and hemodynamic mechanisms of salt-dependent hypertension. In preliminary experiments the applicants continuously monitored mean arterial pressure (MAP), heart rate (HR) and cardiac output (CO) in intact (SHAM) and sinoaortic denervated (SAD) rats consuming normal and high salt diets. Increasing dietary salt for two weeks resulted in an immediate and sustained increase in total peripheral resistance (TPR) in SHAM rats, but not hypertension since both HR and CO were decreased. In SAD rats, an equivalent salt-induced increase in TPR was observed, but CO and HR did not fall and salt-dependent hypertension resulted. These results led to the following hypotheses and specific aims. Experiments in Specific Aim 1 will test the hypothesis that increased dietary salt stimulates release of neuropeptide-Y (NPY) from sympathetic vasomotor neurons to cause vasoconstriction in normotensive rats. In protocol 1, the response of hemodynamics (MAP, CO, HR and TPR) and plasma NPY to increased dietary salt in normal rats and rats chronically treated with the NPY Yl receptor antagonist BIPP 3266 will be measured. The effect of BIPP 3266 on the hemodynamic responses to salt will also be studied in rats chronically treated with alpha and beta-adrenergic antagonists, which have been shown to modulate the vasoconstrictor activity of NPY. In protocol 2, the effect of renal and splanchnic denervation on NPY mediated renal and mesenteric vasomotor responses to increased dietary salt respectively will be determined. In these same animals, the applicants will examine vascular Yl receptor MRNA expression using RT-PCR and correlate these findings with vascular sensitivity to NPY. Experiments in Specific Aim 2 will test the hypothesis that chronic salt induced decreases in cardiac output are mediated by baroreflex control of cardiac sympathetic and vagal tone. To test this hypothesis cardiac output, heart rate and arterial pressure will be monitored 24 hours/day in intact and baroreceptor denervated rats consuming normal and high salt diets. Power spectral analysis of heart rate will be preformed to assess the effect of increased salt on cardiac vagal and sympathetic activity throughout the experiment. In these same rats, the effect of long-term pharmacological blockade of M2 muscarinic receptors and beta l adrenergic receptors on cardiac vagal and sympathetic tone respectively (heart rate power spectra), cardiac output and arterial pressure will be examined before and during dietary salt loading. The applicants predict that impaired autonomic control of the heart will result in salt-dependent hypertension due to failure to buffer salt-induced vasoconstriction by a decrease in cardiac output. These experiments will provide important novel information on the role of the autonomic nervous system in the long-term control of hemodynamics under conditions of increased dietary salt.
Showing the most recent 10 out of 25 publications
