ENDOTHELIN-1 PRODUCES HETEROGENEOUS REGIONAL HEMODYNAMIC-EFFECTS IN CONSCIOUS RABBITS

Blood flow in the renal artery, superior mesenteric artery and infra-r enal abdominal aorta of conscious rabbits was measured by Doppler ultr asound. Arterial pressure, heart rate and blood flow responses were as sessed following 0.2 and 0.8 nmol/kg intravenous endothelin-1. The eff ects of the following antagonists on these responses were examined: ph entolamine, propranolol, scopolamine, captopril, nifedipine, indometha cin, the V-1-vasopressin receptor antagonist d(CH2)(5)Tyr(Me)AVP and t he competitive nitric oxide (NO) synthase inhibitor N-G-nitro L-argini ne (NOLA). Hindlimb resistance and arterial pressure responded in two phases, initial vasodilatation followed by vasoconstriction. Renal and mesenteric vasoconstriction occurred without initial vasodilatation. Following 0.2 nmol/kg endothelin-1, arterial pressure decreased by 18. 5 +/- 0.8 mmHg, then increased by 25.2 +/- 1.7 mmHg (n = 27). Heart ra te changed reciprocally. Renal resistance increased by 533 +/- 73% (n = 12). Mesenteric resistance increased by 420 +/- 34%. Hindlimb resist ance decreased 54 +/- 2% (n = 12, all P < 0.01) then increased slightl y (P < 0.05). All changes were greater at 0.8 nmol/kg, particularly th e hindlimb vasoconstriction, The only antagonist to alter significantl y these responses was NOLA, which in the hindlimb attenuated the vasod ilatation and accentuated the vasoconstriction. We conclude that most of the haemodynamic effects of endothelin-1 are direct, but that NO ge nerated by NO synthase causes part of the hindlimb vasodilatation. and that endothelin-1-induced vasoconstriction is attenuated by release o f NO.