CHRONIC ENDOTHELIN-INDUCED PRESSOR AND RENAL ACTIONS IN CONSCIOUS DOGS DO NOT REQUIRE ALTERED ANG-II FORMATION

Plasma endothelin levels are elevated approximately two- to threefold in a number of chronic pathophysiological conditions associated with h ypertension. Results from recent studies indicate an important interac tion between endothelin and the renin-angiotensin system (RAS). The ro le of the RAS in mediating the increases in arterial pressure produced by long-term pathophysiological elevations in circulating levels of e ndothelin is unknown. Therefore, the purpose of this study was to chro nically increase circulating levels of endothelin within the pathophys iological range and determine the long-term cardiovascular and renal a ctions of endothelin in control dogs (n = 6) and in dogs pretreated wi th a converting-enzyme inhibitor (CEI) (n = 6) or CEI + angiotensin II (ANG II) replacement (n = 6). Infusion of endothelin-1 for 8 days at a rate of 2.5 ng.kg(-1).min(-1) increased plasma endothelin from 7.1 /- 0.9 to 19.8 +/- 3.3 pg/ml. In control dogs, endothelin increased me an arterial pressure (MAP) by 19% (90 +/- 2 to 107 +/- 3 mmHg) while d ecreasing renal blood flow (RBF) by 30% and glomerular filtration rate (GFR) by 15-20%. Long-term elevation of circulating endothelin produc ed similar elevations in MAP in dogs pretreated with CEI (+ 16%) or CE I + ANG II (+ 17%). Similar decreases in RBF and GFR also occurred in response to endothelin in all three groups. These results indicate tha t although long-term increases in circulating endothelin within the pa thophysiological range produce significant increases in arterial press ure, this effect does not appear to be mediated by the RAS.