ACTIONS OF THE NOVEL VASODILATOR, FLOSEQUINAN, IN ISOLATED VENTRICULAR CARDIOMYOCYTES

Although the potent vasodilating effect of flosequinan is well charact erised, the positive inotropic action reported is more varied and less well understood. We examined the contractile and electrophysiologic e ffects 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 sulma zole 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 B TS 53554 had positive contractile effects (p < 0.05) in both rat and r abbit 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%, r espectively, greater than the mean basal dL value of 7.38 +/- 0.12%, m ean +/- SE error). However, the combinations of Ro 20-1724 with floseq uinan and Ro 20-1724 with BTS 53554 produced synergistic responses: 71 +/- 10 and 72 +/- 14%, respectively, greater than the mean basal dL v alue (p < 0.05). In contrast, the combinations of either flosequinan o r BTS 53554 with IBMX or sulmazole produced no further increase in con tractile amplitude. Neither flosequinan nor BTS 53554 produced any det ectable increase in cyclic AMP, whereas significant increases were not ed with Ro 20-1724, IBMX, and sulmazole (p < 0.05) in rat cardiomyocyt es. Flosequinan increased beating frequency in rat isolated right auri cles concentration dependently and was significant over the concentrat ion range of 10(-5)-3 x 10(-4) M; flosequinan 3 x 10(-4) M maximally i ncreased the mean frequency of beating by 35% of the predrug value (25 5 +/- 15 beats/min). Flosequinan had no effect on resting membrane pot ential, amplitude, or maximum upstroke velocity in rat isolated left v entricular (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 change s in AP characteristics over the concentration range of 10(-5)-10(-3) M. The positive contractile and electrophysiologic effects of flosequi nan and its major metabolite, BTS 53554, result from selective inhibit ion of the PDE III isoenzyme. However, these effects were observed onl y at increased concentrations and probably have no clinical value. Flo sequinan had a more pronounced effect on chronotropy (10(-5)-3 x 10(-4 ) M) than on contractile function, which was influenced significantly only at an increased concentration (10(-3) M). Potentiation of the res ponse to rolipram, in terms of APD prolongation, may be caused by a no vel mechanism of action such as enhanced intracellular release of Ca2 by flosequinan.