ENDOTHELIN-1 CAUSES A BIPHASIC RESPONSE IN SYSTEMIC VASCULATURE AND INCREASES MYOCARDIAL-CONTRACTILITY IN CONSCIOUS RABBITS

We studied the effects of an intravenous (i.v.) bolus of endothelin-1 (ET-1, 0.2 nmol/kg) in conscious rabbits, measuring arterial blood pre ssure (BP), heart rate (HR), myocardial contractility, and cardiac out put and evaluating direct and indirect effects of ET-1 with pacing and pharmacologic antagonists. ET-1 caused a brief initial decrease in BP of 18 +/- 1 mm Hg, followed by a sustained increase of 26 +/- 3 mm Hg (n = 16, p < 0.001). HR increased initially by 60 1 11 beats/min and then decreased by 68 +/- 6 beats/min (n = 16, p < 0.001). Left ventric ular (LV) dP/dt increased by 2,120 +/- 380 mm Hg/s (n = 5, p < 0.01). LV end-diastolic pressure (LVEDP) increased by 4 +/- 1 mm Hg (n = 5, p < 0.05). Cardiac output (CO) increased initially by 34 +/- 4% and the n decreased by 28 +/- 3% (n = 16, p < 0.001). Total peripheral resista nce (TPR) decreased initially by 34 +/- 3% and then increased by 72 +/ - 13% (n = 16, p < 0.001). Pacing did not alter the effect of ET-1 on arterial BP, LV dP/dt, or LVEDP. The combination of propranolol and sc opolamine significantly reduced the increase and decrease in HR and th e increase in LV dP/dt. None of the antagonists significantly altered the effect of ET-1 on TPR. ET-1 causes brief initial vasodilation and increased myocardial contractility, followed by sustained vasoconstric tion. The vascular effects appear to be of greater significance than t he cardiac effects at the dose used. The vasoconstriction apparently i s a direct effect, whereas the changes in HR are autonomically mediate d and the increase in myocardial contractility is due to both direct a nd reflex effects. The mechanism of the initial vasodilation is uncert ain.