Actions of the novel vasodilator, flosequinan, in isolated ventricular cardiomyocytes.
Although the potent vasodilating effect of flosequinan is well characterised, the positive inotropic action reported is more varied and less well understood. We examined the contractile and electrophysiologic effects of flosequinan and its metabolite, BTS 53554, in cardiomyocytes from either adult male Sprague-Dawley rats (200-250 g) or New-Zealand White rabbits (2-2.5 kg) and compared the effects with those of sulmazole and enoximone [selective phosphodiesterase (PDE) III inhibitors], Ro 20-1724 and rolipram (selective PDE IV inhibitors) and 3-isobutyl-1-methylxanthine (IBMX, nonselective PDE inhibitor). Flosequinan and BTS 53554 had positive contractile effects (p < 0.05) in both rat and rabbit ventricular cardiomyocytes only at the maximum concentration (10(-3) M). Differences were noted between species, however. Flosequinan 10(-3) M had a greater contractile effect than BTS 53554 (10(-3) M) in rabbit cardiomyocytes, but not in rat cardiomyocytes. We studied the interaction of flosequinan or the metabolite with other PDE inhibitors in rat cardiomyocytes. Contractile amplitudes were not significantly different with equimolar concentrations (3 x 10(-4) M) of Ro 20-1724, flosequinan, or BTS 53554 alone (15 +/- 6, 18 +/- 4, and 32 +/- 10%, respectively, greater than the mean basal dL value of 7.38 +/- 0.12%, mean +/- SE error). However, the combinations of Ro 20-1724 with flosequinan and Ro 20-1724 with BTS 53554 produced synergistic responses: 71 +/- 10 and 72 +/- 14%, respectively, greater than the mean basal dL value (p < 0.05). In contrast, the combinations of either flosequinan or BTS 53554 with IBMX or sulmazole produced no further increase in contractile amplitude. Neither flosequinan nor BTS 53554 produced any detectable increase in cyclic AMP, whereas significant increases were noted with Ro 20-1724, IBMX, and sulmazole (p < 0.05) in rat cardiomyocytes. Flosequinan increased beating frequency in rat isolated right auricles concentration dependently and was significant over the concentration range of 10(-5)-3 x 10(-4) M; flosequinan 3 x 10(-4) M maximally increased the mean frequency of beating by 35% of the predrug value (255 +/- 15 beats/min). Flosequinan had no effect on resting membrane potential, amplitude, or maximum upstroke velocity in rat isolated left ventricular (LV) papillary muscle, but at the maximum concentration (10(-3) M), flosequinan decreased action potential duration (APD) at 10, 50, and 75% of repolarization (p < 0.05). BTS 53554 produced no changes in AP characteristics over the concentration range of 10(-5)-10(-3) M.(ABSTRACT TRUNCATED AT 400 WORDS)
Kelso
E J
EJ
Department of Therapeutics and Pharmacology, Queen's University of Belfast, Ireland.
McDermott
B J
BJ
Silke
B
B
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D006321:Heart / Q000187:drug effects*; D006325:Heart Atria / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000166:cytology / Q000201:enzymology; D010210:Papillary Muscles / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D020889:Rolipram; D013268:Stimulation, Chemical; D014665:Vasodilator Agents / Q000494:pharmacology*
D007093:Imidazoles; D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; D011804:Quinolines; D015363:Quinolones; D014665:Vasodilator Agents; C047316:flosequinan; C047317:flosequinoxan; D000262:Adenylyl Cyclases; C029758:sulmazole; D020889:Rolipram