Effects of levosimendan on myocardial contractility and Ca2+ transients in aequorin-loaded right-ventricular papillary muscles and indo-1-loaded single ventricular cardiomyocytes of the rabbit

Effects of levosimendan on myocardial contractility and Ca2+ transients were assessed in the ventricular myocardium of the rabbit. Levosimendan at and above 0.1 mu M had a concentration-dependent positive inotropic effect (PIE) on isolated papillary muscles that had been loaded with aquorin. The maximum inotropic response to levosimendan at 3 mu M was approximately 20% of the maximum response to isoproterenol (ISO,,), whereas the maximum increase in the amplitude of Ca2+ transients was approximately 11% of ISOmax. For a given PIE, levosimendan increased the amplitude of Ca2+ transients much less than an elevation of [Ca2+](o). Levosimendan did not prolong the relaxation time. Similar results were obtained in single ventricular cardiomyocytes that had been loaded with indo-1. In the presence of the muscarinic receptor agonist carbachol, both the PIE and the increase in the Ca2+ transient induced by levosimendan were markedly attenuated, During wash-out of both carbachol and levosimendan, the contractile force increased conspicuously with little change in the amplitude of Ca2+ transients, an indication that the increase in myofibrillar sensitivity to Ca2+ ions elicited by levosimendan was susceptible to carbachol. Levosimendan at and above 0.03 mu M shifted the concentration-response curve for isoproterenol to the left. Levosimendan had a positive chronotropic effect at 0.01 mu M and higher in the isolated right atrium of the rabbit. These findings indicate that, in addition to the increase by levosimendan of the sensitivity of contractile proteins to Ca2+ ions, the accumulation of cyclic AMP due to the phosphodiesterase-inhibitory action of levosimendan might contribute to the PIE of this drug, (C) 1998 Academic Press.