Reversal of phosphate induced decreases in force by the benzimidazole pyridazinone, UD-CG 212 CL, in myofilaments from human ventricle.
UD-CG 212 Cl, (Fig. 1: 4,5-dihydro-6-[2-(4-hydroxyphenyl)-1 H-benzimidazole-5-yl]-5-methyl-3(2H)-pyridazinone), is the primary metabolite of the positive inotropic agent pimobendan (UDCG 115 BS, Acardi). Our previous studies showed in detergent extracted preparations of canine ventricular muscle that sub-nanomolar concentrations of UD-CG 212 Cl increased submaximal myofilament force, but only when the activation state had been altered by relatively high (5-10 mM) concentrations of inorganic phosphate (Pi) or relatively low (20 microM) concentrations of MgATP. In the present study, we investigated the effects of UD-CG 212 Cl on the pCa-force relationship of detergent extracted bundles of human cardiac fibers before and after addition of Pi. As expected, treatment with 5 mM Pi depressed maximal force at pCa 4.5 by 27.0 +/- 0.4% (mean +/- SEM). Force generated at the half-maximally activating Ca2+ concentration (pCa50) of control fibers (5.98 +/- 0.2) was significantly (p < .05) reduced following the addition of 5 mM Pi (pCa50 = 5.69 +/- 0.3). The addition of UD-CG 212 Cl over a range of concentrations (10(-11)-10(-6) M) had no effect on Ca(2+)-sensitivity under control conditions, but in the presence of 5 mM Pi, there was a 23.1 +/- 0.1% increase in the percent maximal force at pCa5.9. Ca(2+)-sensitivity was also significantly increased in the presence of Pi and 10(-8) M UD-CG 212 Cl (pCa50 = 5.74 +/- 0.3, p < .05). We conclude that UD-CG 212 Cl potentially increases sub-maximal force of human ventricular myofilaments with an inotropic action depending on a state of myofilament activation associated with ischemic conditions.
Fraker
L D
LD
Department of Emergency Medicine, College of Medicine, University of Illinois at Chicago 60612, USA.
Van Eyk
J
J
Solaro
R J
RJ
D008841:Actin Cytoskeleton / Q000187:drug effects* / Q000502:physiology; D002118:Calcium / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D006352:Heart Ventricles / Q000187:drug effects; D006801:Humans; D009200:Myocardial Contraction / Q000187:drug effects; D010710:Phosphates / Q000378:metabolism / Q000494:pharmacology*; D011724:Pyridazines / Q000378:metabolism / Q000494:pharmacology*
D002316:Cardiotonic Agents; D010710:Phosphates; D011724:Pyridazines; C041648:pimobendan; C047936:UD CG 212 Cl; D002118:Calcium