Mechanisms of the inotropic effects of UD-CG 212 Cl, an active metabolite of pimobendan, on ferret papillary muscles.
We investigated the effects of an active metabolite of pimobendan, UD-CG 212 Cl, on Ca(2+) transients and tension using the aequorin method. When extracellular [Ca(2+)] ([Ca2+]o) in the Tyrode's solution was 2 mM, UD-CG 212 C1 (10(-7)-10(-4)M) increased the peak of Ca(2+) transients, accompanying a slight increase in peak tension. When [Ca(2+)]o was decreased to 0.5 mM, the twitch-potentiating effect of UD-CG 212 C1 was more remarkable, but the increase in the Ca(2+) transients at low concentrations of UD-CG 212 C1 (10(-7)-10(-6)M) was not significant as it was at 2 mM [Ca2+]o. The effects of UD-CG 212 Cl on the time courses of Ca(2+) transients and tension were evaluated at 0.5 mM [Ca2+]o. UD-CG 212 Cl shortened the decay time of Ca(2+) transients and the time to peak tension. However, the relaxation time was not significantly altered. UD-CG 212 C1 (10(-6)M) did not significantly change the relation between [Ca(2+)]i and tension in tetanic contraction. Therefore, the twitch-potentiating effect of UD-CG 212 Cl might not be due to an increase in the Ca(2+) sensitivity of the contractile elements. The slight increase in cyclic AMP due to the inhibition of phosphodiesterase type III by UD-CG 212 Cl could explain the twitch-potentiating effect and the faster time courses of Ca(2+) transients and tension.
Komukai
K
K
Department of Physiology, The Jikei University School of Medicine, Tokyo, Japan.
Kurihara
S
S
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology*; D000242:Cyclic AMP / Q000096:biosynthesis; D005289:Ferrets; D009200:Myocardial Contraction / Q000187:drug effects*; D010210:Papillary Muscles / Q000187:drug effects* / Q000502:physiology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011724:Pyridazines / Q000378:metabolism* / Q000494:pharmacology*
D002316:Cardiotonic Agents; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; C041648:pimobendan; C047936:UD CG 212 Cl; D000242:Cyclic AMP; D002118:Calcium