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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.

Cardiovascular effects of methylflavonolamine hydrochloride(SIPI-549) in cross-circulated canine atrial and ventricular preparations.