UD-CG 115--a cardiotonic pyridazinone which elevates cyclic AMP and prolongs the action potential in guinea-pig papillary muscle

Abstract

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)