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.