Positive Inotropic Effect of Levosimendan is Correlated to its Stereoselective Ca²⁺‐Sensitizing Effect but not to Stereoselective Phosphodiesterase Inhibition

Abstract

In order to clarify the mechanisms of the positive inotropic actions of levosimendan and its optical isomer, dextrosimendan, we compared their concentration-dependent effects in intact papillary muscles, permeabilized cardiomyocytes and in purified phosphodiesterase enzyme preparations of guinea-pig hearts. In papillary muscles twitch tension increased with EC 50 values of 60 nM and 2.8 mM for levosimendan and dextrosimendan, respectively. Hence, the two enantiomers exhibited a 47 times potency difference in their positive inotropic effects in a preparation where theoretically Ca 2π -sensitization and phosphodiesterase inhibition could both contribute to the positive inotropic effects. In guinea-pig cardiomyocytes, levosimendan and dextrosimendan increased isometric force production (at pCa 6.2) due to Ca 2π -sensitization with EC 50 values of 8.4 nM and 0.64 mM, respectively, with a similar relative potency difference of 76. A major difference appeared in their relative pharmacological potencies, however, when the inhibitory effects of the two enantiomers were assayed on phosphodiesterase III, purified from guinea pig left ventricle (i.e. the phosphodiesterase isoenzyme which is dominant in that tissue). Levosimendan was a 427 times more potent phosphodiesterase inhibitor than dextrosimendan, with IC 50 values of 7.5 nM, and 3.2 mM, respectively. Taken together, our data support the hypothesis that levosimendan and dextrosimendan exert their positive inotropic effects via a stereoselective Ca 2π -sensitizing mechanism and not via stereoselective inhibition of phosphodiesterase III in the myocardium.Levosimendan is a positive inotropic and vasodilatory drug developed for the treatment of acute de novo or decompensated congestive heart failure (Follath et al. 2002). The drug binds to the Ca 2π saturated cardiac isoform of troponin C (Pollesello et al. 1994;Sorsa et al. 2001Sorsa et al. & 2003 and this binding is stereoselective (Sorsa et al. 2004). A correlation between the binding to troponin C and the positive inotropic effect of levosimendan has been established (Haikala et al. 1995a; Levijoki et al. 2000). However, the molecule displays structural similarities with a family of inhibitors of phosphodiesterases, which leads to an alternative hypothesis for its cardiotonic effects that signifies a possible phosphodiesterase inhibitory action (Boknik et al. 1997) and consequent augmentation of the Ca 2π transient. In contrast to this hypothesis, however, several reports show that levosimendan need not increase the intracellular Ca 2π concentration for the development of a sensible positive inotropic effect (Lancaster & Cook 1997;Hasenfuss et al. 1998;Brixius et al. 2002). To elucidate the pharmacological background of levosimendan-induced positive inotropy, the effects of levosimendan and of its active metabolite, OR-1896 as positive inotropes, Ca terase inhibitors were recently critically compared (Szilagyi et al. 2004). This study demonstrated well-pronounced similarities in the concentration dependen...

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“…Positive inotropic action of levosimendan is correlated to its stereoselective binding to Ca 2+ saturated cardiac troponin C resulting in enhanced myocardial Ca 2+ sensization, with levosimendan about 47 times more potent than its stereoisomer dextrosimendan. [5253]…”

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