Anesth Analg 2006;102:676-681
© 2006 International Anesthesia Research Society
doi: 10.1213/01.ane.0000197780.42409.5b
CARDIOVASCULAR ANESTHESIA
Diazepam Enhances Inotropic Responses to Dopamine in Rat Ventricular Myocardium
María Jesús Juan-Fita, PhD,
María Luisa Vargas, PhD, and
Jesús Hernández, PhD
Departamento de Farmacologia, Facultad de Medicina, Murcia (Spain)
Address correspondence and reprint requests to Jesús Hernández, MD, PhD, Departmento de Farmacologia, Facultad de Medicina, Universidad de Murcia, Campus de Espinardo, 30071 Murcia, Spain. Address e-mail to jehernca{at}um.es
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Abstract
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Diazepam inhibits phosphodiesterase type 4 and enhances the effect of some 3',5'-cyclic adenosine monophosphate (cAMP)-dependent positive inotropic drugs. We sought to determine whether diazepam and the selective phosphodiesterase type 4 inhibitor rolipram enhances the contractile response and cAMP levels induced by dopamine in rat myocardium. Dopamine (3–100 µM) produced concentration-dependent positive inotropic effects (–log EC50 = 5.21 ± 0.2, n = 5), which were augmented in the presence of 10 µM diazepam (-log EC50 = 5.40 ± 0.08, n = 6, P < 0.05) or 1 µM rolipram (-log EC50 = 5.41 ± 0.1, n = 6, P < 0.05). The effect of diazepam was not mimicked by 100 µM  -aminobutyric acid nor it was antagonized by a 5 µM concentration of the blockers of central and peripheral type benzodiazepine receptors, flumazenil and PK 11195. cAMP levels (pmol/g) produced by dopamine (744.4 ± 111.8, n = 5) in this tissue were enhanced by the presence of diazepam (1073 ± 97.7, n = 6, P < 0.05) or rolipram (1034.0 ± 245.2, n = 5, P < 0.05). Therefore, diazepam, like rolipram, augments the inotropic and biochemical effects of dopamine in rat myocardium. This effect is not mediated by benzodiazepine receptors but is probably the consequence of the phosphodiesterase type 4 inhibitory activity of diazepam.
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Introduction
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Dopamine increases cardiac contractility by stimulating 3',5'-cyclic adenosine monophosphate (cAMP) production in the myocardium and it has proved to be a useful drug in patients requiring short-term inotropic support (1). Diazepam enhances the effect of some positive inotropic drugs (2–5) as a result of inhibition of the isoenzyme phosphodiesterase (PDE) 4 that is present in the heart and hydrolyzes cAMP (5). Indeed, an inhibitory effect of diazepam on PDE4 has been demonstrated in guinea pig heart (3) and also in mice (6). This inhibitory effect has been shown to have functional relevance because diazepam enhances the effects of cAMP-increasing drugs in a variety of tissues where PDE4 is present, including myocardium and aorta of rats and eosinophils and brain slices of guinea-pigs (2,3,7,8). Even diazepam alone has been shown to enhance cAMP tissue levels in guinea pig brain (8) and rat hypophysis (9). Interestingly, in a recent study we reported an increase in cAMP plasma levels when diazepam was given to anesthetized patients (10). The cardiac effects of dopamine appear to be attributable to presynaptic noradrenaline release and also to direct cardiac stimulation (11). It has been shown that diazepam enhances the cardiac effects of epinephrine and norepinephrine (4), but whether it amplifies the direct cardiac effect of dopamine remains unknown. Because diazepam may be given concomitantly with dopamine in some clinical conditions, such as in the critically ill patient or during surgical anesthesia (12) it would be interesting to determine the combined effect of these two drugs. The aim of the present study, therefore, was to investigate whether diazepam modifies the effects of dopamine on ventricular myocardium. To this end we have studied the effects of dopamine, in the absence and in the presence of diazepam, on the increase of contractile force and cAMP tissue levels in rat myocardium. For comparison, similar studies were conducted with the selective PDE4 inhibitor, rolipram (13). The possible implication of the benzodiazepine receptors of the central type that are coupled to -aminobutyric acid (GABA)-activated chloride channels, as well as those of the peripheral type that are not linked to the GABA receptor complex (14,15), was also investigated.
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Methods
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The study was reviewed and approved by the Ethical Committee of the University of Murcia. Sprague-Dawley rats of either sex (250–350 g) were instantaneously killed by a blow to the head. The chest was opened and the heart was rapidly removed and placed in Tyrode's solution saturated with 95% O2–5% CO2. The free wall of the right ventricle was excised and cut into three strips. All procedures were performed in the presence of Tyrode's solution of the following composition (mM): NaCl 136.9, KCl 5.0, CaCl2 1.8, MgCl2 1.5, NaH2PO4 0.4, NaHCO3 11.9, and dextrose 5.0. Right ventricular strips were mounted longitudinally between 2 platinum electrodes under 1 g tension in Tyrode's solution maintained at 37°C and gassed with 95% O2–5% CO2. The preparations were electrically stimulated (Grass SD-9 stimulator; Grass, West Warwick, RI) at a frequency of 1 Hz, 1 ms of duration and supramaximal (threshold + 25%) voltage. Contractions were measured using a force-displacement transducer (Grass FT-03) and recorded on a Dynograph Beckman polygraph. Tissues were allowed to equilibrate for 45–60 min before drug challenge. The time course of basal ventricular force was investigated in strips from six rats. Basal force (mN) at 1, 2, and 3 h after setting up the tissues was 5.7 ± 0.4, 5.3 ± 0.3, and 5.0 ± 0.5, respectively. Experiments were conducted during the 2-h period of stable contractile force.
Phentolamine 1 µM, corticosterone 30 µM, and desmethylimipramine 2 µM were present throughout the experiments to block  –adrenoceptors and to inhibit extraneuronal and neuronal uptake respectively. Cumulative concentration-response curves to dopamine (3–100 µM) were determined by increasing the concentration of dopamine by 0.5 log unit, stepwise as soon as the response to the previous concentration had stabilized. Concentration-response curves of dopamine were also performed after 10 min in the presence of each of the follow compounds: CGP-20712A, ICI 118,551, haloperidol, GABA, rolipram, clonazepam, midazolam, or diazepam, the last in the absence and in the presence of flumazenil and PK 11195, selective antagonists of the central and peripheral benzodiazepine receptors, respectively. The concentrations of diazepam (10 µM) or rolipram (1 µM) used were in the region of the IC50 values for selective inhibition of PDE4 and an effective inhibition of this enzyme has been demonstrated in previous studies (3,5,7,13). Only one concentration-response curve for dopamine alone or in the presence of each of the above indicated drugs was determined in the same ventricular strip. Also, in every group, each experiment was performed on a right ventricular strip obtained from a different rat heart. Drugs were added to a 30 mL organ bath in a volume smaller than or equal to 0.1 mL. Experiments were terminated by increasing the Ca2+ concentration to 9 mM, which produced a maximal inotropic response and the results are expressed as percentages of this effect. The data were also expressed in mN.
The levels of cAMP were measured by radioimmunoassay (125I-TME-S-cAMP; Diagnostic Pasteur, France) according to the manufacturer's instructions. The experiments were performed with groups of right ventricular strips taken from different animals. cAMP was measured either under control conditions or after a 13-min exposure to 10 µM diazepam or 1 µM rolipram. The incubation time was similar to that generally used for the study of the interaction between sympathomimetic drugs and PDE inhibitors on intracellular cAMP levels (16,17). To investigate the effects of dopamine, this drug was incubated 3 min, or 3 min after a 10 min incubation period with diazepam or rolipram. After incubation with drugs, the tissues were immediately frozen. The preparation was weighed and homogenized in 1.5 mL of cold perchloric acid (0.3 mol/L) using a Polytron homogenizer (setting 4 for 30 s) and then was centrifuged (10,000g, 4°C, 15 min). The supernatants were treated with potassium phosphate until pH 6.2 was reached. The sensitivity of the assay was 2 pmol/mL. Intra- and inter-assay coefficients of variation were 7.7% and 8.2%, respectively. The antibody cross-reacted 100% with 3',5'-cAMP and <0.3% with other nucleotides. cAMP concentrations were expressed in pmol/g of tissue.
The following drugs were used: diazepam, clonazepam, midazolam, and flumazenil, generously supplied by Roche (Madrid, Spain). Dopamine, phentolamine, desmethylimipramine, corticosterone, rolipram, haloperidol, (±)-2-Hydroxy-5-(2-((2-hydroxy-3-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-l)phenoxy) propyl)amino)ethoxy)-benzamide methanesulfonate (CGP20712A), (±)-1-(2,3-(Dihidro-7-methyl-1H-inden-4-yl)oxy)-3-(1-methylethyl)amino)-2-butanol hydrochloride (ICI118,551), 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-iso-quinolinecarboxamide (PK 11195), and GABA were obtained from Sigma Chemical (Madrid, Spain), and dimethyl sulfoxide (DMSO) was obtained from Probus (Barcelona, Spain).
Dopamine, phentolamine, CGP20712A, ICI185,551, desmethylimipramine, haloperidol, and GABA were dissolved in freshly distilled H2O. Diazepam, clonazepam, midazolam, flumazenil, PK 11195, corticosterone, and rolipram were dissolved in DMSO and Tyrode's solution (20% DMSO in Tyrode's solution); this stock solution was diluted into prewarmed and pre-aerated bathing solution to achieve the final concentration desired. The drug was added to the organ bath at an appropriate concentration so that the concentration of DMSO in the test solution was <0.3%, which had no effect on the ventricular preparation.
Results are expressed as mean ± sd. Student's t-test or one-way analysis of variance followed by Tukey's method were used for multiple comparisons. The criterion for significance was that P values should be <0.05.
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Results
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Dopamine (3–100 µM) produced concentration-dependent positive inotropic effects. As seen in Figure 1a, after washing out dopamine, contractility returned to control values. The contractile force (mN) before dopamine (4.7 ± 1.1, n = 5) and after washing (5.1 ± 1.3, n = 5) was not statistically different (P > 0.05). The ß1-adrenoceptor-selective blocker CGP20712A (300 nM) virtually abolished the inotropic effect of dopamine. On the contrary, the ß2-adrenoceptor-selective blocker ICI118551 (50 nM) neither modified the dopamine concentration response curve nor significantly (P > 0.05) changed its –logEC50M (5.20 ± 0.26, n = 7, alone and 5.07 ± 0.11, n = 5, in the presence of ICI118551 (Fig. 1b).
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Figure 1. Effect of dopamine on the basal force of contraction in rat right ventricle strips. a) Representative trace showing the positive inotropic effect of cumulative administration of dopamine that is reversing upon washing. b) Cumulative concentration-response curves for the inotropic activity of dopamine alone and in the presence of either 0,3 µM CGP-20712A and 50 nM ICI 118,551 (ß1- and ß2-adrenoceptors selective blockers, respectively) or 5 µM of the dopamine receptors blocker haloperidol. Inotropic responses are expressed as a percentage of the effect caused by 9 mM Ca 2+. Each point represent the mean value ± sd (vertical bars). *P < 0.05 when compared with dopamine alone.
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Haloperidol, an antagonist of dopamine receptors, was used to examine the possible influence of these receptors on the inotropic effect of dopamine. It was observed that haloperidol (5 µM, n = 5) alone had no effect nor did it alter the inotropic effect of dopamine (-log EC50M 5.20 ± 0.26, n = 7, alone and 5.22 ± 0.11, n = 5, in the presence of haloperidol, P > 0.05) (Fig. 1b).
The positive inotropic effects of dopamine alone and in the presence of 10 µM or 1 µM of diazepam or rolipram, respectively, are illustrated in Figure 2a–c. Both agents, which are devoid of effect when applied alone, enhance the contractile effect of dopamine. Further experiments were conducted, and the results are summarized in Figure 2d. Diazepam, which alone is devoid of inotropic effects in this preparation, enhanced the Emax of dopamine and also increased its –log EC50 (Table 1). Similar results were obtained with rolipram, which also augmented the Emax of dopamine (8.3 ± 1.3 mN, n = 5, alone and 11.5 ± 0.8 mN, n = 6, in the presence of rolipram, P < 0.05) and changed its –log EC50 from 5.20 ± 0.2, n = 5, to 5.41 ± 0.1, n = 6, respectively, in the absence and the presence of rolipram, (P < 0.05). Contractility after Ca+2 administration, however, did not significantly change after the concentration-response curve to dopamine in the presence of rolipram. Indeed, CaCl2 9 mM alone increased contractility from a basal value of 4.8 ± 1.5 mN to 12.3 ± 2.5 mN (n = 5, P < 0.05) and after the concentration response curve of dopamine was determined in the presence of rolipram the increase observed was from 5.3 ± 1.9 mN (basal) to 13.3 ± 3.7 mN (n = 6, P < 0.05). No statistical difference was observed between the two basal values (P > 0.05), neither between the effect of CaCl2 9 mM alone nor after the concentration response curve of dopamine in the presence of rolipram (P > 0.05).
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Figure 2. Increase of the positive inotropic effects of dopamine by 10 µM diazepam and 1 µM rolipram. Original tracings of experiments with dopamine in the absence (a) and presence of diazepam (b) or rolipram (c). Concentration-effect curves for the inotropic responses of dopamine (d) in the absence and presence of diazepam, rolipram, and diazepam solvent dimethyl sulfoxide (DMSO). Concentrations of DMSO were the same as those present in the diazepam solution. Notice that Emax of dopamine is enhanced by diazepam and rolipram. Each point represent the mean value ± sd (vertical bars). *P < 0.05 compared with dopamine alone.
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To establish whether the increase of the positive inotropic effects of dopamine induced by diazepam could be attributed to activation of the benzodiazepine-GABA receptor/chloride channel complex, we studied whether the effect was mimicked by GABA (100 µM) or prevented by the antagonist of this complex, flumazenil (5 µM). These two compounds were themselves devoid of effect in this preparation when applied alone. In addition, GABA did not alter the effect of dopamine (n = 5) nor did flumazenil modify the diazepam induced enhancement of the inotropic effect of dopamine (n = 6). The specific antagonist of the peripheral benzodiazepine receptors PK 11195 (5 µM) was also devoid of effect on its own and did not alter the effect of dopamine in the presence of diazepam (n = 6) (Table 1, Fig. 3).
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Figure 3. Concentration-effect curves for the inotropic effect of dopamine in the absence and in the presence of -aminobutyric acid (GABA) or diazepam alone and in combination with a 5 µM concentration of the blockers of the central and peripheral type benzodiazepine receptors flumazenil or PK 11195 respectively. Each point represents the mean value ± sd (vertical bars). *P < 0.05 when compared to dopamine alone.
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To ascertain whether the positive inotropic effect of dopamine was enhanced by other benzodiazepines, we studied the interaction of dopamine with a 10 µM concentration of either clonazepam or midazolam. This concentration of the two drugs was devoid of effect alone and did not enhance the inotropic effect of dopamine because the Emax of dopamine is 8.5 ± 1.3 mN (n = 5) in the absence of benzodiazepines and 7.0 ± 2.0 mN (n = 5, P > 0.05) and 7.5 ± 1.3 mN (n = 5, P > 0.05) in the presence of clonazepam or midazolam, respectively. The –log EC50 of dopamine (5.20 ± 0.17, n = 5) was not significantly changed by the presence of clonazepam (5.15 ± 0.15, n = 5, P > 0.05) or midazolam (5.07 ± 0.20, n = 5, P > 0.05).
To investigate whether the inotropic effect of dopamine and its modification by diazepam or rolipram correlated with tissue levels of cAMP we studied the effect of dopamine at 10 µM, which is a concentration approximately equivalent to its EC50 obtained from inotropic results, in the absence and presence of either diazepam or rolipram.
The cAMP content in the right ventricle of rat heart was 585.7 ± 160.7 pmol/g (n = 11), which was not significantly modified by the presence of 10 µM of diazepam (509.3 ± 84.5 pmol/g, n = 6, P > 0.05) or 1 µM of rolipram (536.4 ± 134.4, pmol/g, n = 9, P > 0.05) However, dopamine increased cAMP concentrations in this preparation and the effect was augmented in the presence of diazepam (10 µM) or rolipram (1 µM). DMSO, used as a solvent for diazepam and rolipram, did not produce a significant effect on its own nor did it alter the effect of dopamine on the tissue level of cAMP in our experiments (Fig. 4).
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Figure 4. Diazepam (Dz, 10 µM) and rolipram (R, 1 µM) augment the dopamine-evoked (DA, 10 µM) increase in 3',5'-cyclic adenosine monophosphate (cAMP) concentrations in right ventricle of the rat heart. Diazepam solvent dimethyl sulfoxide (DMSO) is devoid of effect. Number on columns represents the number of rats. Values are mean ± sd (vertical bars). Significance level P < 0.05 (*) is shown between the indicated groups.
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Discussion
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The results of the present study demonstrate that diazepam enhances the inotropic response and cAMP accumulation induced by dopamine in the right ventricular myocardium of the rat. The contractile effect of dopamine (1–100 µM) was completely blocked by the highly selective ß1-adrenoceptor antagonist CGP-20712A but was not modified by the selective ß2- adrenoceptor antagonist ICI 118551. This is consistent with previous findings showing that dopamine at the same concentrations used in our study produced a positive chronotropic effect in rat right atria, which was mainly attributable to ß1-adrenoceptor activation (11). Dopamine can also stimulate -adrenoceptors that are present in the rat heart, thus producing an increase of cardiac contractility (18). In our study however, the presence of the nonselective -adrenoceptor blocker phentolamine precluded this possibility. Also, the possible dopamine-induced catecholamine release did not play a role in our results because it was blocked by the presence of desipramine (11). In accord with previous experimental evidence (11), our results indicate that dopamine receptors do not play a significant role in the inotropic effect of dopamine, as this effect was not affected by the presence of the dopamine receptor antagonist haloperidol.
We have shown that diazepam inhibits PDE4 (3), which is the main isoenzyme responsible for modulating the amplitude and duration of the inotropic effect of different ß-adrenoceptor agonists in the rat heart (4,19). Recently, however, it has been shown that depending on the nature of an agonist, the ß1-adrenoceptor agonists can couple differentially to Gs protein and their effects could be differentially affected by the inhibition of a given PDE (20). Indeed, milrinone (10 µM) enhances the positive inotropic effect of norepinephrine (5) but not that of the isoprenaline (16) in rat right ventricular myocardium. Thus, the way in which the PDE4 inhibitory activity of diazepam affects the inotropic response to dopamine was not previously known but it was investigated in the present study by examining the combination of dopamine with diazepam or the selective PDE4 inhibitor rolipram in rat myocardium. We used diazepam and rolipram at concentrations of 10 µM and 1 µM, which are similar to their respective Ki values for inhibition of PDE4 and are the same concentrations used in previous studies to inhibit this enzyme (3,13). These drugs are devoid of effect alone, which is consistent with the notion that inhibition of PDE4 only increases contractility in the presence of a cAMP dependant positive inotropic drug or when PDE3 is simultaneously inhibited (5). Diazepam, however, like the selective PDE4 inhibitor rolipram, enhances the positive inotropic effects of dopamine in rat right ventricular myocardium. The results support previous findings showing that diazepam enhances the inotropic response elicited by cAMP increasing drugs such as noradrenaline, adrenaline, tyramine, isoprenaline, or forskolin (2,4,5) but not that of non-cAMP-related inotropic drugs such as ouabain or CaCl2 (4). Midazolam at a concentration larger than that required to induce surgical anesthesia (21) failed to enhance the contractile effect of dopamine and clonazepam was also ineffective. This is consistent with the view that, among benzodiazepines, diazepam is the most potent inhibitor of PDE4. Other compounds in this group were devoid of PDE4 inhibition or produced an effect only at concentrations very much larger than those obtained in clinical practice (3).
The biochemical effect of diazepam at a concentration of 10 µM, which failed to modify cAMP tissue levels on its own, became evident in our results when cAMP production was stimulated by dopamine. Consistent with these findings, there is evidence indicating an enhancement by diazepam of the enhancement of cAMP-levels induced by certain drugs such as adenosine in slices of cerebral cortex (8) or isoprenaline, forskolin, noradrenaline, adrenaline, and tyramine in the right ventricle of the rat heart (2,4,5). Similar findings have been obtained with 1 µM rolipram, which did not modify cAMP content when applied alone but increased the cAMP production elicited by dopamine. This agrees with previous results showing that rolipram, which alone is devoid of effect, enhances the effects of isoprenaline (16) and noradrenaline (19) on cAMP levels in rat ventricular myocardium and indicates that diazepam mimics the effects of the typical PDE4 inhibitor rolipram.
The diazepam-induced enhancement of the positive inotropic effect of dopamine is not GABA-dependent, as it is not mimicked by GABA nor is it antagonized by flumazenil, which is an effective antagonist of the effects mediated by the benzodiazepine-GABA receptor/chloride channel complex (14). In our study, the peripheral, non-GABA-related, benzodiazepine binding site does not seem to be involved because the specific peripheral antagonist PK 11195 (15) had no influence on the functional responses of diazepam. Therefore, the results of the present study do not involve benzodiazepine receptors of the central or peripheral type.
From our results, it can be concluded that diazepam, like rolipram, enhances the inotropic effect of dopamine in the rat heart presumably attributable to inhibition of PDE4 activity. This does not seem to be a general effect of benzodiazepines but is, rather, specific to diazepam. In humans, however, only the combination of dopamine with PDE3 inhibitors has been studied and indeed it produces some clinically beneficial cardiac effects (22,23). PDE4 is also present in human heart (24) and PDE4 inhibitors could affect cardiac contractility or augment the effect of cAMP-dependent positive intropic drugs. Interestingly, diazepam (10 mg) increases cardiac contractility in patients with mild heart failure (25). The concentration of diazepam used in the present study was 2.5 µg/mL, which could well be reached when this drug is given during surgical anesthesia (10,21); however, the clinical relevance of the interaction described in the present work remains to be determined.
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Footnotes
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Accepted for publication October 26, 2005.
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References
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|---|
- Stevenson LW. Clinical use of inotropic therapy for heart failure: looking backward or forward? Circulation 2003;108:367–72.[Free Full Text]
- Martínez E, Peñafiel R, Collado MC, Hernández J. Diazepam potentiates the positive inotropic effect of isoprenaline in rat ventricle strips: role of cyclic AMP. Eur J Pharmacol 1995;282:169–75.[Web of Science][Medline]
- Collado MC, Beleta J, Martínez E, et al. Functional and biochemical evidence for diazepam as cyclic nucleotide phosphodiesterase type 4 inhibitor. Br J Pharmacol 1998;123:1047–54.[Web of Science][Medline]
- Marín J, Hernández J. Diazepam potentiates the effects of endogenous catecholamines on contractility and cyclic AMP levels in rat ventricular myocardium. Naunyn-Schmiedebergs Arch Pharmacol 2002;365:260–8.[Web of Science][Medline]
- Juan-Fita MJ, Vargas ML, Hernández J. Comparative actions of diazepam and other phosphodiesterase inhibitors on the effects of noradrenaline in rat myocardium. Pharmacol Toxicol 2003;93:23–8.[Web of Science][Medline]
- Cherry JA, Thompson BE, Pho V. Diazepam and rolipram differentially inhibit cyclic AMP-specific phosphodiesterases PDE4A1 and PDE4B3 in the mouse. Biochim Biophys Acta 2001;1518:27–35.[Medline]
- Galindo A, Vargas ML, García-Stañ J, Hernández J. Synergistic interaction of diazepam with 3'-5'-cyclic adenosine monophosphate-elevating agents on rat aortic rings. Eur J Pharmacol 2001;428:269–75.[Web of Science][Medline]
- York MJ, Davies LP. The effect of diazepam on adenosine uptake and adenosine-stimulated adenylate cyclase in guinea-pig brain. Can J Physiol Pharmacol 1982;60:302–7.[Web of Science][Medline]
- Vargas ML, Abella C, Hernández J. Diazepam increases the hypothalamic-pituitary-adrenocortical (HPA) axis activity by a cyclic AMP-dependent mechanism. Br J Pharmacol 2002;133:1355–61.[Web of Science]
- Carceles MD, Ribó AR, Dávalos R, et al. Effect of diazepam on adenosine 3'-5'-cyclic monophosphate (cAMP) plasma levels in anesthetized patients. Clin Ther 2004;26:737–43.[Web of Science][Medline]
- Habuchi Y, Tanaka H, Nishio M, et al. Dopamine stimulation of cardiac ß-adrenoceptors: the involvement of sympathetic amine transporters and the effect of SKF38393. Br J Pharmacol 1997;122:1669–78.[Web of Science][Medline]
- Reynolds JEF. Martindale: extra pharmacopoeia, 31st ed. London: Pharmaceutical Press, 1996.
- Beavo JA. Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms. Physiol Rev 1995;75:725–48.[Abstract/Free Full Text]
- Teuber L, Watjens F, Jensen LH. Ligands for the benzodiazepine binding site-a survey. Curr Pharm Des 1999;5:317–43.[Web of Science][Medline]
- Parola AL, Yamamura HI. Molecular properties of mitochondrial benzodiazepine receptors. In: Giensen-Crouse E. Ed. Peripheral benzodiazepine receptors. London: Academic Press, 1993:3–26.
- Katano Y, Endoh M. Effects of a cardiotonic quinolinone derivative Y-20487 on the isoproterenol-induced positive inotropic action and cyclic AMP accumulation in rat ventricular myocardium: comparison with rolipram, Ro 20-1724, milrinone and isobutylmethylxantine. J Cardiovasc Pharmacol 1992;20:715–22.[Web of Science][Medline]
- Verde I, Vandecasteele G, Lezoualc’h F, Fischmeister R. Characterization of the cyclic nucleotide phosphodiesterase subtypes involved in the regulation of the L-type Ca2+ current in rat ventricular myocytes. Br J Pharmacol 1999;127:65–74.[Web of Science][Medline]
- Terzic A, Pucéat M, Vassort G, Vogel S. Cardiac 1-adrenoceptors: an overview. Pharmacol Rev 1993;45:147–75.[Web of Science][Medline]
- Monguillo M, McSorley T, Evellin S, et al. Fluorescence resonance energy transfer-based analysis of cAMP dynamics in live neonatal rat cardiac myocytes reveals distinct function of comparmentalized phosphodiesterases. Circ Res 2004;95:67–75.[Abstract/Free Full Text]
- Joseph S, Lynham J, Grace A, et al. Markedly reduced effects of (-)-isoprenaline but not of (-)-CGP12177 and unchanged affinity of ß-blockers at Gly389-ß1-adrenoceptors compared to Arg389-ß1-adrenoceptors. Br J Pharmacol 2004;142:51–6.[Web of Science][Medline]
- Samuelson P, Reves J, Kouchoukos N, et al. Hemodynamic responses to anesthetic induction with midazolam or diazepam in patients with ischemic heart disease. Anesth Analg 1981;60:802–9.[Abstract/Free Full Text]
- Takamatsu I, Karasawa F, Okuda T. Dopamine may preserve the myocardial oxygen balance better than dobutamine when administered with milrinone. Can J Anaesth 2002;49:968–72.[Web of Science][Medline]
- Karasawa F, Okuda T, Tsutsui M, et al. Dopamine stabilizes milrinone-induced changes in heart rate and arterial pressure during anaesthesia with isofluorane. Eur J Anaesthesiol 2003;20:120–3.[Web of Science][Medline]
- Lugnier C, Muller B, Le Bec A, et al. Characterization of indolidan- and rolipram-sensitive cyclic nucleotide phosphodiesterases in canine and human cardiac microsomal fractions. J Pharmacol Exp Ther 1993;265:1142–51.[Abstract/Free Full Text]
- Sumin AN, Khairedinova OP, Galimzianov DM. Effects of diazepam on intracardiac hemodynamics in patients with chronic cardiac failure. Klin Med 2003;81:26–30.
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Abstract
Introduction
