Endothelin-1 has a unique oxygen-saving effect by increasing contractile efficiency in the isolated rat heart

Abstract

Background - The effect of endothelin (ET)-1 on cardiac energetics is not fully understood. Methods and Results - In isolated, coronary-perfused rat hearts, we measured left ventricular contractility index (Emax), pressure-volume area (PVA), and myocardial oxygen consumption (MV̇o2) before and after administration of ET-1 (1×10-9 mol/L). ET-1 increased Emax by 48±16% (P<0.01) and the total MV̇o2 by 24±11% (P<0.01). The MV̇o2-PVA relations were linear both before and after ET-1 (r>0.99). ET-1 shifted MV̇o2-PVA upward, increasing the MV̇o2 intercept by 24±13%. At the same time, ET-1 decreased the slope (S), with 1/S (contractile efficiency) being 46±5% before and 56±5% after ET-1 (P<0.01). ET-1-induced increases in Emax and in contractile efficiency were abolished by an ETA receptor blocker (S-0139) but not by an ETB blocker (BQ-788). Although high [Ca2+] perfusion increased Emax and the intercept to the same extent as ET-1, it did not change S. NG-Nitro-L-arginine (an inhibitor of nitric oxide synthase) increased the coronary perfusion pressure as much as ET-1, but S again remained unchanged. Dimethylamyloride (Na+/H+ exchanger inhibitor) partially blocked the positive inotropic effect of ET-1 but not the ET-1-induced increase in the contractile efficiency. Conclusions - Agonistic effects of ET-1 on the ETA receptor economized the chemomechanical conversion efficiency of the left ventricular unit myocardium by a mechanism independent of the Na+/H+ exchanger. This unique oxygen-saving effect of ET-1 may play an adaptive role in the failing myocardium, in which local accumulation of ET-1 is present.