Positive inotropic and hemodynamic properties of flosequinan, a new vasodilator, and a sulfone metabolite.
Flosequinan, a new orally active vasodilator, and its sulfone metabolite were evaluated for inotropic activity in isolated ferret papillary muscles and pentobarbital anesthetized open-chest dogs. In vitro, flosequinan and its sulfone derivative increased tension development in a concentration-dependent manner (1-50 microM) in electrically stimulated papillary muscles pretreated with the beta-adrenergic blocking agent atenolol (2 microM). Peak increases in tension of 75 +/- 17%, and 111 +/- 46% with potencies (EC50) of 15 and 10 microM were observed for flosequinan and its metabolite, respectively. In vivo, flosequinan increased left ventricular dP/dtmax (74 +/- 12%) and right ventricular contractile force (CF) (104 +/- 10%) after administration of 1.875 mg/kg, i.v. Inotropic activity was dose-dependent and remained elevated for at least 60 min postinfusion. Flosequinan also increased heart rate (HR) (14 +/- 2%) and reduced mean arterial pressure (-9 +/- 3%). The i.v. potency of flosequinan (ED50 = 0.45 mg/kg) and its metabolite (ED50 = 0.38 mg/kg) were similar to that of the inotropic vasodilator amrinone (ED50 = 0.38 mg/kg). Inotropic activity was not significantly altered by pretreatment with propranolol (0.5 mg/kg) and atropine (1.0 mg/kg), further supporting the in vitro data indicating that flosequinan can directly stimulate myocardial contractility independent of beta-adrenergic receptor activation. Additional hemodynamic studies were conducted in an acute heart failure model produced by an overdose of propranolol. Flosequinan (2 mg/kg, i.v.) increased cardiac output (CO) (50 +/- 9%) and stroke volume (SV) (29 +/- 8%) while reducing total peripheral vascular resistance (TPR) (-36 +/- 4%), right atrial pressure (-62 +/- 5%), and left ventricular end-diastolic pressure (LVEDP) (-41 +/- 2%).(ABSTRACT TRUNCATED AT 250 WORDS)
Falotico
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Research Laboratories, Ortho Pharmaceutical Corporation, Raritan, New Jersey 08869.
Haertlein
B J
BJ
Lakas-Weiss
C S
CS
Salata
J J
JJ
Tobia
A J
AJ
D000676:Amrinone / Q000494:pharmacology; D000758:Anesthesia; D000818:Animals; D005289:Ferrets; D006333:Heart Failure / Q000188:drug therapy / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D066298:In Vitro Techniques; D007262:Infusions, Intravenous; D008297:Male; D020105:Milrinone; D009200:Myocardial Contraction / Q000187:drug effects*; D010210:Papillary Muscles / Q000187:drug effects; D010424:Pentobarbital; D011728:Pyridones / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*
D011728:Pyridones; D011804:Quinolines; D014665:Vasodilator Agents; C047316:flosequinan; D010424:Pentobarbital; D020105:Milrinone; D000676:Amrinone