Abstract

Endothelin-1 (ET-1) is a positive inotrope in normal hearts; however, the direct 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_A and ET_B receptor blocker (L-754,142) in seven conscious dogs before and 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 (τ). LV contractile performance, measured by the slopes of LV pressure (P)-volume (V) relation (E_ES), dP/dt_max-end-diastolic V relation (dE/dt_max), and stroke work-end-diastolic V relation, was also unaffected. After CHF, when the plasma ET-1 was significantly increased 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) and total systemic resistance (0.084 ± 0.022 versus 0.065 ± 0.15 mm Hg/ml/min). The τ (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 versus 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 cardiac effect. However, after CHF, elevated endogenous ET-1 produces arterial vasoconstriction, slows LV relaxation, and depresses LV contractile performance. Thus, elevated endogenous ET-1 may contribute to the functional impairment in CHF in this canine model.