The cardiovascular effects of
SIPI-549 [4'-methyl-7-(2-hydroxy-3-isopropylaminoproxy)-
flavone hydrochloride] were investigated in isolated canine atrial and ventricular muscles perfused with heparinized arterial blood from a donor dog. When
SIPI-549 was administered intravenously to the intact donor dog, a slight
hypotension was induced in a dose range of 0.01 to 3 mumol/kg. At the same time, slight negative chronotropic and inotropic responses appeared in isolated and perfused atria, suggesting a
cardiac depressant action. Direct administration of
SIPI-549 into the cannulated sinus node artery of the isolated atrium produced negative inotropic and biphasic chronotropic responses in a dose related manner (0.01-1 mumol).
SIPI-549 also induced a dose-dependent decrease in developed tension of the isolated left ventricle. The SIPI-549-induced negative chronotropic and inotropic effects were not modified by
atropine in doses which blocked
carbachol-induced negative chronotropic and inotropic effects. The SIPI-549-induced positive chronotropic effects were inhibited by
propranolol but significantly potentiated by
imipramine treatment, indicating that a large dose of
SIPI-549 produces a release of
catecholamine via a non-
tyramine like action. Large doses of
SIPI-549 did not significantly affect
norepinephrine-induced positive chronotropic effects. These results indicate that
SIPI-549 may have non-
cholinergic cardiac depressant properties and no beta-
adrenoceptor blocking activity. However, it appears to elicit a release of
catecholamines in a non-
tyramine-like manner at relatively large doses.