Mechanisms of endothelin-1-induced decrease in contractility in adult mouse ventricular myocytes


Department of Cardiovascular Pharmacology, Yamagata University School of Medicine, 2-2-2 Iida-nishi Yamagata 990-9585, Japan. E-mail:


Background and purpose:

The potent vasoconstrictor polypeptide endothelin-1 (ET-1) plays an important pathophysiological role in progression of cardiovascular diseases and elicits prominent effects on myocardial contractility. Although ET-1 produces a positive inotropy in cardiac muscle of most mammalian species, it induces a sustained negative inotropy in mice. This study was performed to gain an insight into the cellular mechanisms underlying the negative inotropy in adult mouse ventricular myocytes.

Experimental approach:

Cell shortening and Ca2+ transients were simultaneously recorded from isolated mouse ventricular myocytes loaded with the Ca2+-sensitive fluorescent dye indo-1.

Key results:

ET-1 decreased cell shortening in a concentration-dependent manner (pD2 value of 10.1). The ET-1-induced decrease in cell shortening was associated with a decrease in Ca2+ transients. In addition, the Ca2+ transient/cell-shortening relationship was shifted to the right by ET-1, indicating decreased myofilament Ca2+ sensitivity. The instantaneous relationship of the rising phase of the Ca2+ transient and cell shortening was shifted to the right by ET-1. Decreased Ca2+ transients and cell shortening induced by ET-1 were markedly attenuated by the specific Na+/Ca2+ exchange inhibitor SEA0400.

Conclusions and implications:

ET-1-induced negative inotropy in mouse ventricular myocytes was mediated by decreased Ca2+ transients and myofilament Ca2+ sensitivity. These data are entirely consistent with the involvement of increased Ca2+ extrusion via the Na+/Ca2+ exchanger in the ET-1-mediated decrease in Ca2+ transients. Decreased Ca2+ sensitivity may be due to retardation of cell shortening in response to a rise in Ca2+ transients.

British Journal of Pharmacology (2007) 152, 456–463; doi:10.1038/sj.bjp.0707392; published online 16 July 2007