ET-1 increases distensibility of acutely loaded myocardium: a novel ETA and Na+/H+ exchanger-mediated effect

This study investigated, in rabbit papillary muscles (n = 61) and human auricular strips (n = 7), effects of endothelin-1 (ET-1; 0.1-10 nM) on diastolic myocardial properties. ET-1 (1 nM) was also given in the presence of selective ET(A) or ET(B) antagonism, nonselective ET(A)/ET(B) antagonism, and Na(+)/H(+) exchanger inhibition. Effects of 6.3 mM Ca(2+) were also studied. ET-1 dose dependently increased inotropism. In contrast to baseline, in the presence of ET-1, resting tension (RT) decreased, after an isometric twitch, 3.4 +/- 1.4, 6.9 +/- 1.5, and 12.5 +/- 3.1% with 0.1, 1, and 10 nM, respectively, reflecting an increase in myocardial distensibility. ET-1 effects were abolished with selective ET(A) as well as with nonselective ET(A)/ET(B) antagonism, whereas they were still present with ET(B) antagonism. Na(+)/H(+) exchanger inhibition abolished ET-1 effects on distensibility, whereas it only partially inhibited positive inotropic effect. Ca(2+) increased inotropism to a similar extent to ET-1 (1 nM) but did not affect distensibility. ET-1 therefore increased diastolic distensibility of acutely loaded human and nonhuman myocardium. This effect is mediated by ET(A) receptors, requires Na(+)/H(+) exchanger activation, and cannot be elicited by Ca(2+).