Subcellular mechanism of the species difference in the contractile response of ventricular myocytes to endothelin-1.

Abstract

The aim of the experiments was to compare the effects of endothelin and alpha-adrenoceptor stimulation on the contraction and inositol phosphate turnover of cardiomyocytes enzymatically isolated from rat and guinea-pig hearts. The effects of agonists on the contraction amplitude of warmed (32 degrees C), electrically stimulated (0.5 Hz) myocytes was recorded using a video-edge detection system. Phosphoinositide hydrolysis was measured in suspensions of myocytes prelabelled with myo-[2(-3)H]-inositol. A doubling of contraction amplitude was observed in rat ventricular myocytes in response to maximally effective concentrations of either endothelin-1 (10 nM) or phenylephrine (1 mM). In rat myocytes, prazosin prevented the effect of phenylephrine but not the effect of endothelin-1. Reversal of the maximal inotropic effect of endothelin was slow (halftime for reversal 11.5 +/- 4.5 min) compared with phenylephrine (3.4 +/- 1.1 min). Endothelin (10 nM) added at the peak effect of phenylephrine produced no further increase in contraction amplitude. The half-time for the reversal of the effect of phenylephrine plus endothelin in these experiments was not significantly different from that with endothelin alone (12.8 +/- 4.0 min). This indicates that phenylephrine did not interact with endothelin binding. Phosphoinositide hydrolysis was increased in rat myocytes by either endothelin or phenylephrine. In guinea-pig myocytes, endothelin-1 stimulated phosphoinositide hydrolysis but did not induce an inotropic response, whereas phenylephrine gave neither an increase in phosphoinositide hydrolysis nor an inotropic effect. We conclude that the observations in rat myocytes are consistent with different receptors for endothelin-1 and phenylephrine, but a common final pathway through the inositol phosphate system for the inotropic effect.(ABSTRACT TRUNCATED AT 250 WORDS)