Differential effects of d- and l-pimobendan on cardiac myofilament calcium sensitivity.
The effects is of the optical isomers of pimobendan (UD-CG 115 BS), an inotropic agent, were studied on the electrical and mechanical activity of intact and detergent-skinned preparations of cardiac muscle from guinea pig and dog. Racemic pimobendan has been shown to increase contractile force and to potentiate slow action potentials (AP) induced by stimulation of papillary muscle partially depolarized with 25 mM [K]o. These effects are shown in this study to be mainly due to the l-optical isomer of pimobendan. When slow APs were maximally stimulated by 1 microM isoproterenol, addition of either the d- or l-isomer of pimobendan did not affect the slow AP parameters. However, under these conditions, contractile force was significantly increased to 124% of control by the d-isomer and to 184% of control by the l-isomer. These results suggest that pimobendan may have direct effects on the myofilaments and that these effects are dependent on the optical isomer of the compound. To test this directly, the effects of d- and l-pimobendan were compared on Ca++-activated force developed by detergent-skinned heart muscle fibers. Submaximal force developed at constant Ca++ was increased by both optical isomers, but the l-isomer had a significantly greater Ca++-sensitizing effect. For example at pCa 6.75 force was 270% of control in the presence of the d-isomer and 400% of control in the presence of the l-isomer. At pCa 5, there was no effect of either isomer on force developed by the skinned fiber preparations.(ABSTRACT TRUNCATED AT 250 WORDS)
Fujino
K
K
Department of Physiology and Biophysics, College of Medicine, University of Cincinnati, Ohio.
Sperelakis
N
N
Solaro
R J
RJ
D008841:Actin Cytoskeleton / Q000187:drug effects*; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002118:Calcium / Q000494:pharmacology*; D003599:Cytoskeleton / Q000187:drug effects*; D004285:Dogs; D004594:Electrophysiology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D007536:Isomerism; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D011433:Propranolol / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology*
D011724:Pyridazines; C041648:pimobendan; D011433:Propranolol; D007545:Isoproterenol; D002118:Calcium