Diazepam potentiates the positive inotropic effect of isoprenaline in rat ventricle strips: role of cyclic AMP

Martinez, Ester; Peñafiel, Rafael; Collado, M Carmen; Hernández, Jesús

doi:10.1016/0014-2999(95)00325-f

Cited by 23 publications

(19 citation statements)

References 25 publications

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“…It has also been shown that diazepam potentiates the inotropic response to isoprenaline in the rat heart and that this effect is mediated through an enhancement of intracellular cyclic AMP levels [19]. Additional evidence suggests that the enhancement of cyclic AMP levels is due to the behaviour of diazepam to act as a selective type IV cyclic nucleotide phosphodiesterase inhibitor in cardiac tissue, thus improving the production of ATP [20].…”

Section: Introductionmentioning

confidence: 99%

The effect of diazepam on myocardial function and coronary vascular tone after endotoxemia in the isolated rat heart model

Neethling

Hodge

2010

Inflamm. Res.

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Section: Introductionmentioning

confidence: 99%

The effect of diazepam on myocardial function and coronary vascular tone after endotoxemia in the isolated rat heart model

Neethling

Hodge

2010

Inflamm. Res.

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“…Potentiation of the contractile effect of histamine by diazepam through increase of the cyclic AMP level in a guinea pig heart preparation was also reported [12]. Other authors report that diazepam potentiates the positive inotropic effect induced by β-adrenoceptor agonists through enhancing cyclic AMP production in the rat ventricular strip [24]. These phenomenon directly relate to the positive inotropic effects induced by diazepam in vivo.…”

Section: Discussionmentioning

confidence: 71%

“…There is an explanation of why diazepam produces the positive inotropic effects. Diazepam mediates the positive inotropic effects via catecholamines activating β-adrenoceptors and histamine activating histaminergic H 2 receptors that, in turn, produce cyclic adenosine monophosphate [12,24]. On the other hand, the mechanism of the negative inotropic effect of diazepam is still unclear.…”

Section: )mentioning

confidence: 96%

Negative Inotropic Effect of Diazepam in Isolated Guinea Pig Heart.

Hara¹,

Kobayashi²,

Ooshiro³

et al. 2001

The Journal of Veterinary Medical Science

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ABSTRACT. The inotropic effect of diazepam, a benzodiazepine derivative, and its mechanism of action were examined using guinea pig heart and single ventricular cell preparations. In Langendorff hearts and right ventricular free-wall preparations, diazepam (10 to 100 µM) produced a monophasic negative inotropic effect in a concentration dependent manner. Neither a central type (flumazenil 1 µM) nor a peripheral type (PK11195 10 µM) of benzodiazepine receptor antagonist antagonized the monophasic negative inotropic effects of diazepam. Diazepam (10 to 100 µM) shortened action potential duration of papillary muscle in a concentration dependent manner. In isolated single ventricular cells, diazepam (30 and 100 µM) inhibited the calcium current (I Ca ) in a concentration dependent manner. Diazepam produced a significant decrease in I Ca elicited by first depolarizing pulses, however, the decrease of I Ca was not augmented during a train of depolarizing pulses. Thus, diazepam appears to produce a tonic block of cardiac calcium channels and the mode of inhibition is clearly different from the use-dependent block of verapamil. From these results, it was concluded that diazepam produces a monophasic negative inotropic effect that is independent of the benzodiazepine receptor, and is probably mediated through an inhibition of I Ca in guinea pig heart preparations.KEY WORDS: calcium current, diazepam, heart, negative inotropic effect, patch clamp method.

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“…Racemic [ 3 H]‐rolipram was a special preparation made by Amersham and had a specific activity of 15.8 Ci mmol −1 . All other drugs and reagents used were from the same sources previously stated (Gristwood et al , 1992; Martinez et al , 1995b).…”

Section: Methodsmentioning

confidence: 99%

“…In previous work, we showed that diazepam potentiates the inotropic response in the rat heart, as well as the enhancement of intracellular levels of cyclic AMP induced by isoprenaline and forskolin (Martinez et al , 1995a) or tyramine (Martinez et al , 1995b). Other authors have also found evidence that diazepam increases the effect of adenosine 3′: 5′‐cyclic monophosphate (cyclic AMP)‐producing agents such as noradrenaline (Elgoyhen & Adler‐Graschinsky, 1989) or adenosine (York & Davies, 1982).…”

Section: Introductionmentioning

confidence: 91%

Functional and biochemical evidence for diazepam as a cyclic nucleotide phosphodiesterase type 4 inhibitor

Collado

Beleta

Martinez

et al. 1998

British J Pharmacology

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1 The responses of the electrically-driven right ventricle strip of the guinea-pig heart to diazepam were recorded in the absence and in the presence of di erent selective cyclic nucleotide phosphodiesterase (PDE) inhibitors. 2 Diazepam, at concentrations ranging from 1 mM to 100 mM, was devoid of e ect on the contractile force in this preparation. 3 Conversely, diazepam (5 mM ± 100 mM) produced a consistent positive inotropic response in the presence of a concentration (1 mM), that was without e ect in the absence of diazepam, of either of the selective PDE 3 inhibitors milrinone or SK&F 94120, but not in the presence of the selective PDE 4 inhibitor rolipram. 4 This e ect of diazepam was not g-aminobutyric acid (GABA)-dependent, since it was neither mimicked nor potentiated by GABA, and was not a ected by either a high concentration (5 mM) of the antagonists of the benzodiazepine/GABA/channel chloride receptor complex, picrotoxin,¯umazenil and b-carboline-3-carboxylic acid methyl ester (bCCMe), or by the inverse agonists, b-carboline-3-carboxylic acid N-methylamide (bCCMa) and methyl 6,7-dimethoxy-4-ethyl-b-carboline-3-carboxylate (DMCM, 0.1 mM). Furthermore, a speci®c antagonist of the peripheral benzodiazepine receptors, PK 11195 (5 mM), did not in¯uence the e ect of diazepam. 5 Biochemical studies with isolated PDEs, con®rmed that diazepam selectively inhibits type 4 PDE from guinea-pig right ventricle rather than the other PDEs present in that tissue. The compound inhibited this enzyme in a non-competitive manner. Diazepam was also able to inhibit PDE 5, the cyclic GMP speci®c PDE absent from cardiac muscle, with a potency close to that shown for PDE 4. 6 Diazepam displaced the selective type 4 PDE inhibitor, rolipram from its high a nity binding site in rat brain cortex membranes, and also potentiated the rise in cyclic AMP levels induced by isoprenaline in guinea-pig eosinophils, where only type 4 PDE is present. 7 The PDE inhibitory properties of diazepam were shared, although with lower potency, by other structurally-related benzodiazepines, that also displaced [ 3 H]-rolipram from its high a nity binding site. The order of potency found for these compounds in these assays was not related to their potencies as modulators of the GABA receptor through its benzodiazepine binding site. 8 The pharmacological and biochemical data presented in this study indicate that diazepam behaves as a selective type 4 PDE inhibitor in cardiac tissue and this e ect seems neither to be mediated by the benzodiazepine/GABA/channel chloride receptor complex nor by peripheral type benzodiazepine receptors.

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Diazepam potentiates the positive inotropic effect of isoprenaline in rat ventricle strips: role of cyclic AMP

Cited by 23 publications

References 25 publications

The effect of diazepam on myocardial function and coronary vascular tone after endotoxemia in the isolated rat heart model

The effect of diazepam on myocardial function and coronary vascular tone after endotoxemia in the isolated rat heart model

Negative Inotropic Effect of Diazepam in Isolated Guinea Pig Heart.

Functional and biochemical evidence for diazepam as a cyclic nucleotide phosphodiesterase type 4 inhibitor

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