Differential inotropic effects of flosequinan in ventricular muscle from normal ferrets versus patients with end‐stage heart failure

1 In right ventricular papillary muscles from control ferrets, flosequinan (10−7−10−4 m) produced a concentration-dependent positive inotropic effect (10−5 m = 153 ± 24, 10−4 m = 198 ± 44% increase in isometric tension; control tension = 100%; n = 11) associated with a corresponding increase in amplitude of the intracellular Ca2+ (Ca2+i) transient recorded with aequorin (10−5 m = 133 ± 11, 10−4 m = 187 ± 36% increase in Ca2+i transient; n = 11). 2 The positive inotropic effect of flosequinan in control ferret ventricular muscle was neither blocked by propranolol (6 × 10−7 m), nor associated with the abbreviation of the Ca2+i transient and contraction that is typical of catecholamines. 3 Neither flosequinan (n = 12) nor BTS 53 554, its sulphone metabolite (n = 6) produced a positive inotropic effect or altered the time course of contraction in myocardium from the hearts of patients with end-stage failure. 4 In contrast to milrinone, which produces a positive inotropic effect via phosphodiesterase inhibition, the unresponsiveness of myopathic human myocardium to flosequinan was not restored after intracellular adenosine 3′:5′-cyclic monophosphate (cyclic AMP) levels were increased by prior treatment with forskolin (n = 13). 5 Taken together, these data indicate that flosequinan has a direct positive inotropic effect that is Ca2+-dependent, but independent of changes in intracellular cyclic AMP concentrations. 6 The positive inotropic effect may be species-dependent or altered by the presence of hypertrophy and/or heart failure. However, when used therapeutically in patients with severe heart failure, our data suggest that flosequinan should not adversely affect myocardial oxygen consumption through direct or catecholamine-mediated actions on the heart.