Studies on the cardiac actions of flosequinan in vitro

Abstract

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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“…Flow rate was 1 ml/min throughout. Fractions of 0.5 ml were collected, analyzed and stored as previously described [26]. The cyclic nucleotide PDE isoenzymes were identified according to the nomenclature proposed by Beavo et al [4].…”

Effects of SCA40 on human isolated bronchus and human polymorphonuclear leukocytes: comparison with rolipram, SKF94120 and levcromakalim

“…Fractions of 0.5 ml were collected, analysed andstored as previously described (Gristwood et at., 1992;Cortijo et at., 1993). The cyclic nucleotide PDE isoenzymes were identified according to the nomenclature adopted by Beavo & Reifsnyder (1990).…”

β-Adrenoceptor stimulation up-regulates phosphodiesterase 4 activity and reduces prostaglandin E 2 -inhibitory effects in human neutrophils

“…The PDEs were eluted against a linear sodium acetate gradient (50-1000 mM). Fractions were collected, analyzed and stored as previously described (Gristwood et al 1992). The cyclic nucleotide PDE isoenzymes were identified according to Beavo et al (1994).…”