EFFECTS OF A NEW CARDIOTONIC AGENT 1,2-DIHYDRO-6-METHYL-2-OXO-5-[IMIDAZO(1,2-A)PYRIDIN-6-YL]-3-PYRIDINE CARBONITRILE HYDROCHLORIDE MONOHYDRATE (E-1020) ON CONTRACTILE-FORCE AND CYCLIC-AMP METABOLISM IN CANINE VENTRICULAR MUSCLE

E-1020, a newly synthesized imidazopyridinylpyridine or imidazopyridine derivative (structurally closely related to the bipyridine derivative milrinone) increased the force of contraction and cyclic AMP levels in a concentration-dependent manner in the isolated canine ventricular trabeculae electrically driven at 0.5 Hz at 37°C. The concentration-response curve for the increase in force of contraction by E-1020 was biphasic. The maximal positive inotropic effect (PIE) of E-1020 is comparable to that of milrinone, and its potency is 3-fold less than that of milrinone, but 10-fold higher than that of amrinone. The time course of increases in force of contraction induced by E-1020 was coincident with that of cyclic AMP accumulation. The concentration-response curve for the PIE of E-1020 was superimposable to that of cyclic AMP accumulation. A β-adrenoceptor antagonist, (±)-bupranolol (3×10-7 mol/l), did not affect the PIE of E-1020. The increase in the force of contraction and accumulation of cyclic AMP produced by E-1020 were inhibited by a muscarinic receptor agonist, carbachol. The relationship between the force of contraction and cyclic AMP levels in the presence of E-1020 was not modified by addition of carbachol or isoproterenol. E-1020 shifted the concentration-response curve for isoproterenol to the left. E-1020 shortened the total duration of contraction and relaxation time of isometric contractions. These findings indicate that cyclic AMP is essentially involved in the PIE of E-1020 on the canine ventricular muscle, although the possible involvement of a cyclic AMP-independent mechanism can not be excluded. © 1990, The Japanese Pharmacological Society. All rights reserved.