Cardiac effects of the novel pyridazinone derivative 6-[4-[2-[3-(5-chloro-2-cyanophenoxy)-2-hydroxypropylamino]- 2- methylpropylamino]phenyl]-4,5-dihydro-5-methyl-3(2H) pyridazinone monoethyl maleate and its metabolite in isolated heart preparations of guinea pigs and dogs.
The cardiovascular effects of 6-[4-[2-[3-(5-chloro-2-cyanophenoxy)-2- hydroxypropylamino]-2-methylpropylamino]phenyl]-4,5-dihydro- 5-methyl-3(2H) pyridazinone monoethyl maleate (salt) (TZC-5665, CAS 114856-47-2) and its main metabolite in human, M-2, were investigated in isolated atrial and ventricular muscles of guinea pigs and dogs, in guinea pig atrial and right ventricular papillary muscles. TZC-5665 showed negative chronotropic and inotropic effects, whereas M-2 showed a potent positive inotropic effect with a slight positive chronotropic effect. The positive inotropic effect of M-2 was not modified by phentolamine, propranolol and cimetidine, but completely depressed by carbachol. In blood-perfused dog heart preparations, M-2 increased the contractile force and coronary blood flow of paced papillary muscles and sinus rate. Although TZC-5665 scarcely affected the contractile force and sinus rate, it increased coronary blood flow. TZC-5665 scarcely affected atrio-ventricular (AV) conduction time, whereas M-2 slightly shortened AV conduction time. The rate of ventricular automaticity was slightly increased by M-2, but suppressed by TZC-5665 at higher doses. TZC-5665 showed a non-selective beta-adrenoceptor blocking activity comparable to that of propranolol in guinea-pig atrial and tracheal preparations. In enzyme preparations, TZC-5665 and M-2 were more potent and selective inhibitors of phosphodiesterase (PDE) III than milrinone. Combination of beta-adrenoceptor blocking effect of TZC-5665 and positive inotropic effect of M-2 could be useful in the treatment of congestive heart failure by mutual prevention of undesirable effects.
Ishimori
T
T
Pharmacological Research Department, Teikoku Hormone Mfg. Co. Ltd., Kawasaki, Japan.
Gotanda
K
K
Sasaki
T
T
Shinbo
A
A
Asano
H
H
Miyazawa
K
K
Miyasaka
K
K
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D001283:Atrioventricular Node / Q000187:drug effects; D002317:Cardiovascular Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects; D004285:Dogs; D004347:Drug Interactions; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology; D010210:Papillary Muscles / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011724:Pyridazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D012849:Sinoatrial Node / Q000187:drug effects; D014132:Trachea / Q000187:drug effects
D000319:Adrenergic beta-Antagonists; D002317:Cardiovascular Agents; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; C088090:TZC 5665; D010727:Phosphoric Diester Hydrolases