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 microM had a concentration-dependent positive inotropic effect (PIE) on isolated papillary muscles that had been loaded with aqeuorin. The maximum inotropic response to levosimendan at 3 microM was approximately 20% of the maximum response to isoproterenol (ISOmax), 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 microM shifted the concentration-response curve for isoproterenol to the left. Levosimendan had a positive chronotropic effect at 0.01 microM 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.
Department of Pharmacology, Yamagata University School of Medicine, Japan.
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D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000331:Aequorin; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D004305:Dose-Response Relationship, Drug; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006835:Hydrazones / Q000494:pharmacology*; D007211:Indoles; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D010210:Papillary Muscles / Q000187:drug effects* / Q000378:metabolism; D011724:Pyridazines / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology; D011817:Rabbits; D000077464:Simendan; D013829:Thiadiazines / Q000494:pharmacology
D002316:Cardiotonic Agents; D006835:Hydrazones; D007211:Indoles; D011724:Pyridazines; D011804:Quinolines; D013829:Thiadiazines; C070609:EMD 53998; D000077464:Simendan; D000331:Aequorin; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D007545:Isoproterenol; C048960:indo-1; D002118:Calcium