STUDIES ON THE CARDIAC ACTIONS OF FLOSEQUINAN INVITRO

1 We have investigated the in vitro cardiac actions of flosequinan and of its major metabolite in man, BTS 53554. 2 Positive inotropic activity was seen with flosequinan in guinea-pig isolated ventricles, the threshold concentration for effect being less than 1 x 10(-5) M. BTS 53554 was approximately half as potent as the parent compound. 3 In guinea-pig working whole hearts flosequinan increased left ventricular dp/dt(max), indicating a positive inotropic action. This effect was accompanied by increases in heart rate, cardiac output and stroke volume. 4 The virtual complete inhibition of inotropic responses to flosequinan and BTS 53554 by carbachol suggests that these responses are adenosine 3':5'-cyclic monophosphate (cyclic AMP)-mediated. 5 Flosequinan was shown to increase calcium inward current in guinea-pig ventricle, an action consistent with a cyclic AMP involvement in the response. 6 The inotropic activity of flosequinan was not potentiated by the selective phosphodiesterase (PDE) III inhibitor SK&F 94120, a result which indicates that flosequinan does not increase cyclic AMP concentrations via stimulation of adenylate cyclase. 7 Flosequinan inotropic responses were potentiated by rolipram, a selective PDE IV inhibitor, a result consistent with flosequinan being itself a PDE III inhibitor. 8 Biochemical studies with purified enzymes confirmed that flosequinan and BTS 53554 are relatively selective inhibitors of PDE III. 9 A comparison of pharmacological and biochemical data for both flosequinan and BTS 53554 indicates that their PDE III inhibitory potency is sufficient to account for their inotropic activity.