SUBCELLULAR MECHANISM OF THE SPECIES-DIFFERENCE IN THE CONTRACTILE RESPONSE OF VENTRICULAR MYOCYTES TO ENDOTHELIN-1

The aim of the experiments was to compare the effects of endothelin an d alpha-adrenoceptor stimulation on the contraction and inositol phosp hate turnover of cardiomyocytes enzymatically isolated from rat and gu inea-pig hearts. The effects of agonists on the contraction amplitude of warmed (32-degrees-C), electrically stimulated (0.5 Hz) myocytes wa s recorded using a video-edge detection system. Phosphoinositide hydro lysis was measured in suspensions of myocytes prelabelled with myo-[2- H-3]-inositol. A doubling of contraction amplitude was observed in rat ventricular myocytes in response to maximally effective concentration s of either endothelin-1 (10nM) or phenylephrine (1 mM). In rat myocyt es, prazosin prevented the effect of phenylephrine but not the effect of endothelin-1. Reversal of the maximal inotropic effect of endotheli n was slow (half-time for reversal 11.5 +/- 4.5 min) compared with phe nylephrine (3.4 +/- 1.1 min). Endothelin (10nm) added at the peak effe ct of phenylephrine produced no further increase in contraction amplit ude. The half-time for the reversal of the effect of phenylephrine plu s endothelin in these experiments was not significantly different from that with endothelin alone (12.8 +/- 4. 0 min). This indicates that p henylephrine did not interact with endothelin binding. Phosphoinositid e hydrolysis was increased in rat myocytes by either endothelin or phe nylephrine. In guinea-pig myocytes, endothelin-1 stimulated phosphoino sitide hydrolysis but did not induce an inotropic response, whereas ph enylephrine gave neither an increase in phosphoinositide hydrolysis no r an inotropic effect. We conclude that the observations in rat myocyt es are consistent with different receptors for endothelin-1 and phenyl ephrine, but a common final pathway through the inositol phosphate sys tem for the inotropic effect. There appears to be a lack of coupling b etween phosphoinositide hydrolysis and contraction in guinea pig myocy tes in addition to an absence of functional alpha-adrenoceptors.