The positive inotropic effect of pimobendan involves stereospecific increases in the calcium sensitivity of cardiac myofilaments.
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]0 and maximally activating concentrations of isoproterenol, isometric force was increased further by addition of 50 microM 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 microM 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 microM 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 l isomer. The Ca2+-sensitizing effect of l-pimobendan on skinned fiber preparations was substantially greater than that of the d isomer.(ABSTRACT TRUNCATED AT 250 WORDS)
Solaro
R J
RJ
Department of Physiology and Biophysics, University of Illinois College of Medicine, Chicago 60680.
Fujino
K
K
Sperelakis
N
N
D008841:Actin Cytoskeleton / Q000502:physiology*; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002118:Calcium / Q000502:physiology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003599:Cytoskeleton / Q000502:physiology*; D004285:Dogs; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000648:ultrastructure; D011724:Pyridazines / Q000494:pharmacology*; D013237:Stereoisomerism
D002316:Cardiotonic Agents; D011724:Pyridazines; C041648:pimobendan; D002118:Calcium