The positive inotropic effect of pimobendan involves stereospecific increases in the calcium sensitivity of cardiac myofilaments

Abstract

We have studied the effect of pimobendan (UD-CG 115 BS) on the electrical, mechanical, and biochemical activity of intact and detergent-skinned preparations of cardiac muscle. Racemic pimobendan increased the contractile force of guinea pig papillary muscle preparations and this positive inotropic action was associated with potentiation of the Ca2+-dependent slow action potentials (APs). However, in the presence of 25 mM [K]o and maximally activating concentrations of isoproterenol, isometric force was increased further by addition of 50 μM pimobendan with no effect on the slow action potential. Experiments with chemically skinned heart Muscle fibers showed that pimobendan. in a dose-dependent manner, increased active tension developed at submaximally activating concentrations of Ca2+. The tension-cost (unit increase in ATPase rate/unit increase in force) was unchanged in the presence of pimobendan. Force-pCa and ATPase-pCa relations of skinned fiber preparations contracting isometrically were shifted to the left by 0.15-0.20 pCa units in the presence of 50 μM pimobendan. The mechanism for this effect was shown to be an increase in the Ca affinity of the regulatory binding sites of troponin C (TNC). These effects are due mainly to the l optical isomer of pimobendan. Addition of either the d or l isomer of pimobendan to preparations. maximally stimulated by 1 μM isoproterenol, did not affect the slow AP parameters, but did increase contractile force to 124% of control by the d isomer and to 184% of control by the d isomer. The Ca2+-sensitizing effect of l-pimobendan on skinned liber preparations was substantially greater than that of the d isomer. Our results indicate that the Ca2+-sensitizing action of pimobendan (a) is due mainly to the l isomer, (b) involves direct effects on the Ca2+-binding to TNC. and (c) involves specific interactions with domains of the regulatory protein complex. © 1989 Raven Press. Ltd., New York.