Differential inhibition by the Rho kinase inhibitor Y-27632 of the increases in contractility and Ca2+ transients induced by endothelin-1 in rabbit ventricular myocytes

The role of Rho kinase activation in the regulation of cardiac contractility and Ca²⁺ signaling remains unclear, whereas its role in smooth muscle regulation has been well documented. To study the potential role of Rho kinase in the regulation of cardiac contractility and Ca²⁺ transients induced by endothelin-1 (ET-1) and isoproterenol, we used the Rho kinase inhibitor Y-27632 in rabbit ventricular myocardium and myocytes loaded with indo-1/AM. Y-27632 (3–30 M) inhibited significantly the baseline contractility and Ca²⁺ transients. Furthermore, Y-27632 suppressed the increase in contractility and Ca²⁺ transients induced by ET-1 in a concentration-dependent manner, when it was used in a concentration at which it did not affect the effects of isoproterenol via -adrenoceptors. In the presence of Y-27632, ET-1 increased cell shortening in the absence of an increase in Ca²⁺ transients. This is an indication that the increase in myofilament Ca²⁺ sensitivity induced by ET-1 is less susceptible to the inhibitory action of Y-27632. These findings imply that the Rho kinase activation may partially contribute to the ET-1-induced regulation of contractility, primarily due to an ET-1-induced increase in Ca²⁺ transients in rabbit ventricular myocardium.