Cardiovascular effects of the new cardiotonic agent 1,2-dihydro-6-methyl-2-oxo-5-(imidazo[1,2-a]pyridin-6-yl)-3-pyridine carbonitrile hydrochloride monohydrate. 1st communication: studies on isolated guinea pig cardiac muscles.
Cardiotonic effects and the mechanism of action of 1,2-dihydro-6-methyl-2-oxo-5-(imidazo[1,2-a]pyridin-6-yl)-3-pyridine carbonitrile hydrochloride monohydrate (E-1020), a new cardiotonic agent, were investigated in vitro. E-1020 (10(-7)-10(-4) mol/l) produced a concentration-dependent positive inotropic effect in papillary muscles. E-1020 also caused an increase in contractile force in the right atria which was accompanied by small increases in spontaneous beating rate. The inotropic effect of E-1020 on papillary muscles was not altered by treatment with beta-adrenoceptor or histamine H2-receptor blockade, but was attenuated by the muscarinic agonist, carbachol. E-1020, like isoprenaline (isoproterenol, Iso), restored the contraction of papillary muscles which had been arrested in a high-potassium solution. The inotropic response of papillary muscles to Iso was potentiated by pretreatment with E-1020 at a minimally-effective inotropic concentration (3 x 10(-7) mol/l). E-1020 did not affect the activity of dog kidney Na+, K+-ATPase. On the other hand, the compound specifically inhibited the cyclic AMP-specific isoenzyme (fraction III) of phosphodiesterase and caused an elevation of cyclic AMP content in guinea pig hearts. These results indicate that E-1020 is a potent cardiotonic agent with a minor chronotropic effect and that its inotropic action is mainly mediated by the rise in cardiac cyclic AMP content due to the inhibition of cyclic AMP-specific phosphodiesterase.
Ogawa
T
T
Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.
Ohhara
H
H
Tsunoda
H
H
Kuroki
J
J
Shoji
T
T
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006635:Histamine H2 Antagonists / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology; D010042:Ouabain / Q000494:pharmacology; D010210:Papillary Muscles / Q000187:drug effects; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
D000319:Adrenergic beta-Antagonists; D002316:Cardiotonic Agents; D006635:Histamine H2 Antagonists; D007093:Imidazoles; D011728:Pyridones; C059498:olprinone; D010042:Ouabain; D002217:Carbachol; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D000254:Sodium-Potassium-Exchanging ATPase; D007545:Isoproterenol