Triphasic inotropic response of guinea-pig papillary muscle to murrayaquinone-A isolated from Rutaceae

Murrayaquinone-A, a carbazole alkaloid, was found to produce a triphasic inotropic response (first positive, second negative and third positive phases) of guinea-pig papillary muscle that normally paced at a slow rate of 0.2 Hz in Krebs-Henseleit solution at 30°C. Murrayaquinone-A produced a concentration-dependent (10 −6 M-10 −4 M) positive inotropic effect (pD 2 value 5.27 evaluated at the first phase). The triphasic pattern of inotropism of murrayaquinone-A was unaffected by reserpine, metoprolol or cimetidine treatment. Murrayaquinone-A increased the initial upstroke and the duration of the slow action potential in partially depolarized muscle (external K + = 30 mEq). Murrayaquinone-A did not cause any positive inotropy under anoxic conditions and in the presence of 2,4-dinitrophenol and dicumarol. These results indicated that the triphasic inotropic effect of murrayaquinone-A is not mediated through a receptor mechanism but through a novel mechanism involving mitochondrial ATP production, thereby increasing the slow inward calcium current across the cardiac cell membrane via cyclic AMP converted from mitochondrial ATP.