Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of flosequinan and its sulphone metabolite BTS 53,554, on phosphodiesterase isoenzymes isolated from guinea-pig cardiac and vascular smooth muscle using DEAE-cellulose chromatography was investigated. Zaprinast and milrinone showed peak I and peak III selectivity, and IBMX non-selective activity respectively, against both cardiac and vascular smooth muscle isoenzymes, as expected for these reference inhibitors. Flosequinan and BTS 53,554 demonstrated non-selective inhibition with similar potency against both cardiac and vascular smooth muscle isoenzymes and, overall, were the least potent compounds tested. The high inhibitory concentrations observed (IC50 peak III 660 microM for cardiac tissue and 230 microM for vascular smooth muscle with flosequinan) relative to its clinically effective plasma concentration (10 microM) questions the relevance of phosphodiesterase inhibition to the efficacy of flosequinan in heart failure.
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PMID:Effect of flosequinan upon isoenzymes of phosphodiesterase from guinea-pig cardiac and vascular smooth muscle. 131 14

1. We have investigated the in vitro cardiac actions of flosequinan and of its major metabolite in man, BTS 53554. 2. Positive inotropic activity was seen with flosequinan in guinea-pig isolated ventricles, the threshold concentration for effect being less than 1 x 10(-5) M. BTS 53554 was approximately half as potent as the parent compound. 3. In guinea-pig working whole hearts flosequinan increased left ventricular dp/dtmax, indicating a positive inotropic action. This effect was accompanied by increases in heart rate, cardiac output and stroke volume. 4. The virtual complete inhibition of inotropic responses to flosequinan and BTS 53554 by carbachol suggests that these responses are adenosine 3':5'-cyclic monophosphate (cyclic AMP)-mediated. 5. Flosequinan was shown to increase calcium inward current in guinea-pig ventricle, an action consistent with a cyclic AMP involvement in the response. 6. The inotropic activity of flosequinan was not potentiated by the selective phosphodiesterase (PDE) III inhibitor SK&F 94120, a result which indicates that flosequinan does not increase cyclic AMP concentrations via stimulation of adenylate cyclase. 7. Flosequinan inotropic responses were potentiated by rolipram, a selective PDE IV inhibitor, a result consistent with flosequinan being itself a PDE III inhibitor. 8. Biochemical studies with purified enzymes confirmed that flosequinan and BTS 53554 are relatively selective inhibitors of PDE III. 9. A comparison of pharmacological and biochemical data for both flosequinan and BTS 53554 indicates that their PDE III inhibitory potency is sufficient to account for their inotropic activity.
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PMID:Studies on the cardiac actions of flosequinan in vitro. 132 61

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)
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PMID:Actions of the novel vasodilator, flosequinan, in isolated ventricular cardiomyocytes. 776 1