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 x 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 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.
Perreault
C L
CL
Harvard-Thorndike Laboratory, Beth Israel Hospital, Harvard Medical School, Boston, MA 02215.
Hague
N L
NL
Loh
E
E
Hunneyball
I M
IM
Sim
M F
MF
Morgan
J P
JP
D000818:Animals; D002118:Calcium / Q000502:physiology; D005576:Colforsin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005289:Ferrets; D006333:Heart Failure / Q000503:physiopathology*; D006352:Heart Ventricles / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D020105:Milrinone; D009200:Myocardial Contraction / Q000187:drug effects*; D011728:Pyridones / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology; D013268:Stimulation, Chemical; D014665:Vasodilator Agents / Q000494:pharmacology*
D011728:Pyridones; D011804:Quinolines; D015363:Quinolones; D014665:Vasodilator Agents; D005576:Colforsin; C047316:flosequinan; C047317:flosequinoxan; D020105:Milrinone; D002118:Calcium