sea-0400 and indo-1

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.. Cell shortening and Ca(2+) transients were simultaneously recorded from isolated mouse ventricular myocytes loaded with the Ca(2+)-sensitive fluorescent dye indo-1.. ET-1 decreased cell shortening in a concentration-dependent manner (pD(2) value of 10.1). The ET-1-induced decrease in cell shortening was associated with a decrease in Ca(2+) transients. In addition, the Ca(2+) transient/cell-shortening relationship was shifted to the right by ET-1, indicating decreased myofilament Ca(2+) sensitivity. The instantaneous relationship of the rising phase of the Ca(2+) transient and cell shortening was shifted to the right by ET-1. Decreased Ca(2+) transients and cell shortening induced by ET-1 were markedly attenuated by the specific Na(+)/Ca(2+) exchange inhibitor SEA0400.. ET-1-induced negative inotropy in mouse ventricular myocytes was mediated by decreased Ca(2+) transients and myofilament Ca(2+) sensitivity. These data are entirely consistent with the involvement of increased Ca(2+) extrusion via the Na(+)/Ca(2+) exchanger in the ET-1-mediated decrease in Ca(2+) transients. Decreased Ca(2+) sensitivity may be due to retardation of cell shortening in response to a rise in Ca(2+) transients.

Topics: Actin Cytoskeleton; Aniline Compounds; Animals; Calcium; Calcium Channel Blockers; Calcium Signaling; Cell Shape; Dose-Response Relationship, Drug; Endothelin-1; Fluorescent Dyes; Heart Ventricles; Indoles; Mice; Myocardial Contraction; Myocytes, Cardiac; Nicardipine; Phenyl Ethers; Sodium-Calcium Exchanger