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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.

Abstract
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.
AuthorsT Ishimori, K Gotanda, T Sasaki, A Shinbo, H Asano, K Miyazawa, K Miyasaka
JournalArzneimittel-Forschung (Arzneimittelforschung) Vol. 44 Issue 5 Pg. 583-8 (May 1994) ISSN: 0004-4172 [Print] Germany
PMID7912931 (Publication Type: Journal Article)
Chemical References
  • Adrenergic beta-Antagonists
  • Cardiovascular Agents
  • Phosphodiesterase Inhibitors
  • Pyridazines
  • TZC 5665
  • Phosphoric Diester Hydrolases
Topics
  • Adrenergic beta-Antagonists (pharmacology)
  • Animals
  • Atrioventricular Node (drug effects)
  • Cardiovascular Agents (pharmacokinetics, pharmacology)
  • Coronary Circulation (drug effects)
  • Dogs
  • Drug Interactions
  • Female
  • Guinea Pigs
  • Heart (drug effects)
  • Heart Rate (drug effects)
  • In Vitro Techniques
  • Male
  • Myocardial Contraction (drug effects)
  • Myocardium (enzymology)
  • Papillary Muscles (drug effects)
  • Phosphodiesterase Inhibitors (pharmacology)
  • Phosphoric Diester Hydrolases (metabolism)
  • Pyridazines (pharmacokinetics, pharmacology)
  • Sinoatrial Node (drug effects)
  • Trachea (drug effects)

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