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

Abstract

tion 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.

Can further benefit be achieved by adding flosequinan to patients with congestive heart failure who remain symptomatic on diuretic, digoxin, and an angiotensin converting enzyme inhibitor? Results of the flosequinan-ACE inhibitor trial (FACET).

“…In one study, flosequinan did not increase contractility with or without forskolin stimulation. 35 In a second report, a positive inotropic action was observed, although only at concentrations somewhat higher than the measured therapeutic range, and forskolin potentiation was present.39 These findings would be consistent with weak phosphodiesterase inhibitor activity.…”

“…In isolated muscle strips from normal animal and human hearts, flosequinan appears to have a dose-dependent, positive inotropic effect, although this is not always observed in the therapeutic concentration range.2035-38 This is associated with a rise in intracellular Ca2+, but it does not appear to be mediated by a cyclic AMP-dependent mechanism because it is not enhanced in the presence of forskolin in most studies. 35,36,38 In muscle harvested from failing human hearts, conflicting findings have been observed. In one study, flosequinan did not increase contractility with or without forskolin stimulation.…”

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“…It has also been shown, by analysis of heart rate variability, to reduce sympathetic activity and augment parasympathetic tone (Binkley et al, 1992). Some studies have demonstrated a positive inotropic action depending on the dosage (Perreault et al, 1991), preparation (Weishaar et al, 1991), and animal species tested (Greenberg et al, 1990). Even using the same invasive technique for assessing changes in contractility in patients has yielded conflicting results (Burstein et al, 1992;Starling, 1992a).…”