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 μM 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 μM was approximately 20% of the maximum response to isoproterenol (ISO(max)), whereas the maximum increase in the amplitude of Ca²⁺ transients was approximately 11% of ISO(max). For a given PIE, levosimendan increased the amplitude of Ca²⁺ transients much less than an elevation of [C²⁺]. 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 μM shifted the concentration-response curve for isoproterenol to the left. Levosimendan had a positive chronotropic effect at 0.01 μM 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.