Altered responsiveness to endothelin-1 of myocardium from pacing-induced heart failure model in the dog.

Abstract

In congestive heart failure, in addition to a compensatory increase in neurohumoral activation, there is an increase in the endothelial-derived vasoconstrictive and positive inotropic substance, endothelin. Whether downregulation of the cardiac inotropic effects of this endothelial-derived substance occurs, as has been shown to occur with neurohumoral beta- and alpha-adrenergic agonists, remains unknown. In this study we investigated the effects of endothelin-1 [dose-response curve (10(-11) to 10(-7) M)] on the contractile characteristics of isolated papillary muscles from normal dogs and from dogs with heart failure induced by pacing overdrive, with or without removing endocardial endothelium from the papillary muscles. Endothelin-1 caused a similar absolute increase in myocardial contractile indices in all four groups, except for shortening, which increased more in muscles with heart failure without endocardial endothelium. However, in muscles with an intact endocardial endothelium, the relative increase was greater in muscles from pacing overdrive dogs (failing) as compared with normal dogs (tension increase of 110% vs. 53%, p < 0.01 and shortening increase of 127% vs. 24%, p < 0.01). Also, failing muscles with intact endocardial endothelium began responding to endothelin-1 at lower endothelin-1 concentrations (10(-10) vs. 10(-9) M) than normal muscles with intact endocardial endothelium. Endocardial endothelial removal increased the contractile effects of endothelin-1, whether this was done in normal or failing myocardium. This study thus indicates that, in contrast to other positive inotropic substances, in this model of heart failure there is an increase in sensitivity and relative response to endothelin-1. It also indicates that although endocardial endothelial removal increases the relative effects of endothelin-1 in both normal and failing myocardium, the increased responsiveness of failing myocardium is not endocardial endothelial dependent.