TY - JOUR T1 - Endogenous Endothelin-1 Depresses Left Ventricular Systolic and Diastolic Performance in Congestive Heart Failure JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1214 LP - 1222 VL - 288 IS - 3 AU - Katsuya Onishi AU - Michiya Ohno AU - William C. Little AU - Che-Ping Cheng Y1 - 1999/03/01 UR - http://jpet.aspetjournals.org/content/288/3/1214.abstract N2 - 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 ETA and ETB 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 (EES), dP/dtmax-end-diastolic V relation (dE/dtmax), 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, EES(3.4 ± 0.4 versus 4.8 ± 0.8 mm Hg/ml), dE/dtmax(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. The American Society for Pharmacology and Experimental Therapeutics ER -