(Verbatim from the application): A major objective of the current proposal is to examine the role of and the mechanisms whereby endothelin B receptors modulate renal-pressure natriuresis and blood pressure regulation. Endothelin- 1 acts through two receptors, ETA and ETB receptors. Both of these receptors are located in the kidney with the highest concentration of ETB receptors existing within the medulla. Although the role of ETA receptors has been well characterized in the pathophysiology of hypertension and other disease states, the physiological importance of ETB receptors in modulating renal-pressure natriuresis and blood pressure regulation is unclear. Preliminary data from our laboratory indicate that the renal production of endothelin is enhanced by chronic sodium loading. Moreover, data from our laboratory and others suggest that chronic ETB receptor blockade results in a salt-sensitive form of hypertension. The exact mechanisms involved in mediating the hypertension induced by chronic ETB receptor blockade, however, are unknown.
Specific aims to be addressed are: 1) To test the hypothesis that the renal endothelin system is upregulated in response to increases in sodium intake. 2) To test the hypothesis that the hypertension induced by chronic ETB receptor blockade is associated with a chronic hypertensive shift in the pressure-natriuresis relationship. 3) To test the hypothesis that the renal medulla plays an important role in mediating the hypertension induced by chronic ETB receptor blockade. 4) To test the hypothesis that reduced nitric oxide synthesis mediates the reduction in renal function and elevation in arterial pressure during ETa receptor blockade-induced hypertension. 5) To test the hypothesis that angiotensin II mediates the reduction in pressure natriuresis and elevation in arterial pressure during chronic receptor blockade-induced hypertension. 6) To test the hypothesis that ETb blockade reduces pressure-induced natriuresis by blunting the transmission of renal perfusion pressure into the renal interstitium. To test these specific hypotheses, an integrated analysis of arterial pressure, renal microcirculatory, hormonal, and sodium excretory function will be determined in a conscious, chronically-instrumented rat model of hypertension induced by chronic ET1 receptor blockade.
