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 degrees 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 beta-adrenoceptor antagonist, (+/-)-bupranolol (3 X 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.
Satoh
H
H
Department of Pharmacology, Yamagata University School of Medicine, Japan.
Endoh
M
M
D000676:Amrinone / Q000494:pharmacology; D000818:Animals; D002046:Bupranolol / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism*; D004285:Dogs; D005260:Female; D006321:Heart / Q000187:drug effects*; D006352:Heart Ventricles / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D007537:Isometric Contraction; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism*; D011728:Pyridones / Q000494:pharmacology*
D002316:Cardiotonic Agents; D007093:Imidazoles; D011728:Pyridones; C059498:olprinone; D002046:Bupranolol; D002217:Carbachol; D000242:Cyclic AMP; D000676:Amrinone; D007545:Isoproterenol