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

Abstract

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 ETA or ETB antagonism, nonselective ETA/ETB antagonism, and Na+/H+ exchanger inhibition. Effects of 6.3 mM Ca2+ 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 ETA as well as with nonselective ETA/ETB antagonism, whereas they were still present with ETB antagonism. Na+/H+ exchanger inhibition abolished ET-1 effects on distensibility, whereas it only partially inhibited positive inotropic effect. Ca2+ 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 ETA receptors, requires Na+/H+ exchanger activation, and cannot be elicited by Ca2+.