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 Ca 2+ ([Ca 2+ ] i ) transient recorded with aequorin (10 −5 m = 133 ± 11, 10 −4 m = 187 ± 36% increase in [Ca 2+ ] 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 [Ca 2+ ] 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 Ca 2+ ‐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.