UD-CG 115--a cardiotonic pyridazinone which elevates cyclic AMP and prolongs the action potential in guinea-pig papillary muscle.
The mechanism of the positive inotropic effect of a benzimidazole-pyridazinone, UD-CG 115, was analysed in the isolated guinea-pig papillary muscle contracting isometrically at a frequency of 0.2 Hz. UD-CG 115 produced a slowly developing and poorly reversible positive inotropic effect increasing with concentration (3-300 mumol/l). The effect amounted to 30 and 74% of the maximum inotropic effect of a standard, dihydroouabain, at 34 and 300 mumol/l, respectively. Low concentrations shortened and 300 mumol/l UD-CG 115 significantly prolonged the duration of contraction. The enhancement of the maximum rate of relaxation, S2, was intermediate between those produced by isoprenaline and dihydroouabain, respectively. UD-CG 115 prolonged the duration of the transmembrane action potential (90% repol .) by up to 22% at 300 mumol/l, whereas an equieffective concentration of isoprenaline did not consistently alter action potential duration. UD-CG 115 increased Vmax and overshoot, and prolonged the duration, of slow action potentials elicited at 24 mmol/l [K]0. The inotropic potency of UD-CG 115 was not significantly changed by reserpine pretreatment of the guinea pig or by the presence of 1 mumol/l(-)-propranolol, 3 mumol/l phentolamine or 10 mumol/l cimetidine. Neither was it reduced by 10 mumol/l TTX. The inotropic effect of 100 mumol/l UD-CG 115 remained unchanged when [K]0 was elevated from 3.2 to 12.0 mmol/l. A sarcolemmal preparation of guinea- pig ventricular Na,K-ATPase was only slightly inhibited by the highest concentration of UD-CG 115.(ABSTRACT TRUNCATED AT 250 WORDS)
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002927:Cimetidine / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D005260:Female; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D010210:Papillary Muscles / Q000378:metabolism / Q000502:physiology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011433:Propranolol / Q000494:pharmacology; D011724:Pyridazines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D012110:Reserpine / Q000494:pharmacology; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013268:Stimulation, Chemical
D002316:Cardiotonic Agents; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; C041648:pimobendan; D002927:Cimetidine; D006632:Histamine; D012110:Reserpine; D002217:Carbachol; D011433:Propranolol; D000242:Cyclic AMP; D000254:Sodium-Potassium-Exchanging ATPase; D007545:Isoproterenol