Temporal changes in atrial EC-coupling during prolonged stimulation with endothelin-1

Endothelin-1 (ET-1) is a potent G(q)-coupled agonist with important physiological effects on the heart. In the present study, we characterised the effect of prolonged ET-1 stimulation on Ca(2+) signalling within acutely isolated atrial myocytes. ET-1 induced a reproducible and complex sequence of effects, including negative inotropy, positive inotropy and pro-arrhythmic spontaneous Ca(2+) transients (SCTs). The negative and positive inotropic effects correlated with the ability of Ca(2+) to propagate from the subsarcolemmal sites where EC-coupling initiates into the centre of the atrial cells. We examined the spatial and temporal properties of the SCTs and observed them to range from elementary Ca(2+) sparks, flurries of Ca(2+) sparks, to Ca(2+) waves and action potential-evoked global Ca(2+) transients. The positive inotropic effect of ET-1 and its ability to trigger SCTs were mimicked by direct stimulation of InsP(3)Rs. An antagonist of InsP(3)Rs prevented the generation of SCTs and partially reduced the positive inotropy evoked by ET-1. Our data suggest that ET-1 engages multiple signal transduction pathways to provoke a plethora of different responses within an atrial myocyte. Some of the actions of ET-1 appear to be due to stimulation of InsP(3)Rs.