Endogenous endothelin-1 depresses left ventricular systolic and diastolic performance in congestive heart failure

Endothelin-1 (ET-1) is a positive inotrope in normal hearts; however, the d irect cardiac effects of endogenous ET-1 in congestive heart failure (CHF) are unknown, We evaluated the cardiac responses to endogenous ET-1 using an ET, and ET, receptor blocker (L-754,142) in seven conscious dogs before an d after pacing-induced CHF. Before CHF, when the plasma ET-1 was 7.3 +/- 1. 7 fmol/ml, L-754,142 caused no significant alterations in heart rate, left Ventricular (LV) end-systolic pressure, total systemic resistance, and the time constant of LV relaxation (tau). LV contractile performance, measured by the slopes of LV pressure (P)-volume M relation (E-ES), dP/dt(max)-end-d iastolic V relation (dE/dt(max)), and stroke work-end-diastolic V relation, was also unaffected. After CHF, when the plasma ET-1 was significantly inc reased to 14.1 +/- 3.0 fmol/ml (p < .05), L-754,142 produced a significant decreases in LV end-systolic pressure (101 +/- 11 versus 93 +/- 8 mm Hg) an d total systemic resistance (0.084 +/- 0.022 versus 0.065 +/- 0.15 mm Hg/ml /min). The tau (42 +/- 12 versus 38 +/- 10 ms), mean left atrial P (22 +/- 5 Versus 18 +/- 4 mm Hg) (p < .05), and minimum LVP were also significantly decreased. After CHF, the slopes of P-V relations, E-ES (3.4 +/- 0.4 versu s 4.8 +/- 0.8 mm Hg/ml), dE/dt(max) (42.4 +/- 7.8 versus 50.0 +/- 7.8 mm Hg /s/ml), and stroke work-end-diastolic V relation (58.1 +/- 3.3 versus 72.4 +/- 5.2 mm Hg) (p < .05) all increased after L-754,142, indicating enhanced contractility. Before CHF, low levels of endogenous ET-1 have little cardi ac effect. However, after CHF, elevated endogenous ET-1 produces arterial v asoconstriction, slows LV relaxation, and depresses LV contractile performa nce. Thus, elevated endogenous ET-1 may contribute to the functional impair ment in CHF in this canine model.