Comparative Actions of Diazepam and Other Phosphodiesterase Inhibitors on the Effects of Noradrenaline in Rat Myocardium

Abstract

Diazepam inhibits different isoforms of the enzyme cyclic nucleotide phosphodiesterase and also potentiates the inotropic effect of endogenous catecholamines in rat heart. In the present study we have examined whether this late effect is the consequence of inhibition of a phosphodiesterase subtype or whether inhibition of several phosphodiesterase subtypes is involved. We compared the effect of diazepam with that of the selective inhibitors of phosphodiesterase1 (MIMX), phosphodiesterase2 (EHNA), phosphodiesterase3 (milrinone) and phosphodiesterase4 (rolipram) on the inotropic effect of noradrenaline in rat ventricle. Both rolipram or diazepam were equipotent and more effective than milrinone in potentiating the inotropic effect of noradrenaline whereas EHNA and MIMX had no effect. The results suggest that the diazepam induced potentiation of the contractile effect of noradrenaline is due principally to inhibition of phosphodiesterase4 isoenzyme activity.We recently demonstrated that diazepam produces an inotropic and biochemical potentiation of endogenous catecholamines, namely noradrenaline and adrenaline (both exogenously applied or released by the indirectly acting sympathomimetic agent tyramine), in rat myocardium (Marín & Hernández 2002). This effect is not due to an enhancement of noradrenaline release at the presynaptic level nor is it mediated by b 2 -adrenoceptors or benzodiazepine receptors of the central or peripheral type (Marín & Hernández 2002). We also showed that diazepam exerts an inhibitory effect on different isoforms of the enzyme cyclic nucleotide phosphodiesterase (phosphodiesterase), including types 1, 2, 3 and 4 which are present in the heart and are involved in the hydrolysis of the cyclic AMP (cAMP) (Collado et al. 1998). This has functional relevance at a number of levels such as guinea-pig eosinophils (Collado et al.1998), rat aorta (Galindo et al. 2001 or the hypothalamicpituitary-adrenocortical axis of the rat . Furthermore, diazepam behaves like the non-selective phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine, in rat myocardium (Marín & Hernández 2002) and this phosphodiesterase inhibitory activity seems to mediate the diazepaminduced potentiation of the effects of certain inotropic agents acting via cAMP release, such as isoprenaline, the direct activator of adenylate cyclase, forskolin (Martinez et al. 1995) and histamine (Hara et al. 1998). Whether this effect is the consequence of inhibition of a particular phosphodiesterase subtype or whether a combined inhibitory action of diazepam on a number of phosphodiesterase subtypes is not Author for correspondence: J. Hernández; Department of Pharmacology; Faculty of Medicine; Campus de Espinardo; Murcia; Spain (fax π34 968 364150, e-mail jehernca/um.es).known. Thus the aim of the present study was to gain an insight into the respective roles of the four different phosphodiesterase subtypes in the diazepam induced potentiation of cAMP-dependent inotropic agents. To this end we compared the effect of diazepam wi...

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