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

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Abstract
1. 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. 2. UD-CG 115 produced a slowly developing and poorly reversible positive inotropic effect increasing with concentration (3–300 μmol/l). The effect amounted to 30 and 74% of the maximum inotropic effect of a standard, dihydroouabain, at 34 and 300 μmol/l, respectively. Low concentrations shortened and 300 μmol/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. 3. UD-CG 115 prolonged the duration of the transmembrane action potential (90% repol.) by up to 22% at 300 μmol/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. 4. The inotropic potency of UD-CG 115 was not significantly changed by reserpine pretreatment of the guinea pig or by the presence of 1 μmol/l (−)-propranolol, 3 μmol/l phentolamine or 10 μmol/l cimetidine. Neither was it reduced by 10 μmol/l TTX. The inotropic effect of 100 μmol/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. 5. Carbachol (0.1–3 μmol/l) inhibited the positive inotropic effect of UD-CG 115, and this antagonism disappeared in the presence of 1 μmol/l atropine. 6. In the presence of a moderately effective concentration of UD-CG 115 (10 μmol/l) the inotropic potencies (-log EC50) of isoprenaline, histamine, and IBMX were all significantly increased by 0.60±0.07, 0.36±0.06, and 0.44±0.06 log units, respectively, whereas that of dihydroouabain was not significantly affected. 7. UD-CG 115 increased the force of the rested-state contraction by augmenting the late component of contraction. 8. Cyclic AMP content determined by radioimmunoassay in individual papillary muscles was raised 1.64-fold in the presence of 10 μmol/l UD-CG 115, but did not significantly increase beyond this level when drug concentration was raised further up to 30-fold. Carbachol prevented the effect of UD-CG 115 on cyclic AMP content. 9. Addition of UD-CG 115 in the presence of the maximally effective concentration of isoprenaline gave a further positive inotropic and klinotropic effect, whereas the phosphodiesterase inhibitor IBMX was without effect on contraction under this condition. 10. These findings are consistent with the proposal that the inotropic action of UD-CG 115 depends on a moderate elevation of cyclic AMP (not involving β-adrenoceptors or histamine-H2-receptors but probably due to phosphodiesterase inhibition) combined with a prolongation of the action potential that augments the inotropic cyclic AMP effect by increasing Ca influx through Ca channels.