Endothelin Antagonists Improve Renal Function in Spontaneously Hypertensive Rats

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Abstract
Abstract Hypertension in the spontaneously hypertensive rat (SHR) is associated with reduced renal excretory function, low renal plasma flow, reduced glomerular filtration rate, and reduced renal interstitial hydrostatic pressure. The mechanisms responsible for these abnormalities in renal function are unknown. The purpose of this study was to determine the role of intrarenal endothelin in altering renal hemodynamic and excretory function in the SHR. Both PD 145065 (an endothelin A and B receptor antagonist) and FR 139317 (a selective endothelin A receptor antagonist) or saline was infused into the renal interstitium of 14- to 16-week-old SHR (n=7) and age-matched Wistar-Kyoto rats (WKY) (n=7). Renal perfusion pressure in some SHR was reduced to that of the WKY by a servocontrol system. At a renal perfusion pressure of 124±4 mm Hg, infusion of PD 145065 (0.03 mg · kg −1 · min −1 ) and FR 139317 (0.02 mg · kg −1 · min −1 ) significantly increased glomerular filtration rate (Δ22%), renal plasma flow (Δ37%), and renal interstitial hydrostatic pressure (from 3.2±0.5 to 5.4±0.6 mm Hg) in the SHR. These changes were associated with significant increases in urine flow, absolute sodium excretion, and fractional excretion of sodium. Similar improvements in renal plasma flow, renal interstitial hydrostatic pressure, and renal excretory function were obtained in the SHR whose renal perfusion pressure was not reduced (n=7). Renal interstitial infusion of endothelin receptor antagonists had no effect on renal hemodynamic or excretory function in the WKY. These data demonstrate that endothelin receptor blockade within the kidney improves renal hemodynamic and excretory function in the SHR. These results suggest that intrarenal endothelin may mediate, in part, the abnormal renal function in the SHR.