In vitro and in vivo vasodilator activity of racemic tramadol and its enantiomers in Wistar rats

Raimundo, Juliana Montani; Sudo, Roberto T.; Pontes, Luana Braga; Antunes, Fernanda; Trachez, Margarete M.; Zapata‐Sudo, Gisele

doi:10.1016/j.ejphar.2005.11.028

Cited by 37 publications

(22 citation statements)

References 16 publications

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“…8 High doses (2 × 10 -4 to 10 -3 M) of (+)-tramadol, but not (-)-tramadol, produce a concentration-dependent relaxation of rat aorta pre-contracted with phenylephrine. 13 In accordance with previous stereoselectivity studies, 4,8,13 R(-) tramadol produced the rather augmented inhibitory effect on the levcromakalim-induced relaxation, compared with the S(+) tramadol enantiomer, even though both R(-) and S(+) tramadol (10 -5 , 5 × 10 -5 M) attenuated the vasorelaxation mediated by levcromakalim in a concentrationdependent manner.…”

Section: Discussionsupporting

confidence: 68%

Inhibitory effect of tramadol on vasorelaxation mediated by ATP-sensitive K+ channels in rat aorta

Cho

Sohn

Park³

et al. 2007

Can J Anesth/J Can Anesth

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Purpose: Tramadol produces a conduction block similar to lidocaine by exerting a local anesthetic-like effect. The aims of this in vitro study were to determine the effects of tramadol on the vasorelaxant response induced by the adenosine triphosphate-sensitive K + (K ATP ) channel opener, levcromakalim, in an endothelium-denuded rat aorta, and to determine whether this effect of tramadol is stereoselective. Methods:The effects of tramadol (racemic, R(-) and S(+): 10 -6 , 10 -5 , 5 × 10 -5 M), and glibenclamide on the levcromakalim dose-response curve were assessed in aortic rings that had been pre-contracted with phenylephrine. In the rings pretreated independently with naloxone, and glibenclamide, the levcromakalim dose-response curves were generated in the presence or absence of tramadol. The effect of tramadol on the dose-response curve of diltiazem was assessed.Results: Racemic, R(-) and S(+) tramadol (10 -5 , 5 × 10 -5 M) attenuated (P < 0.0001) levcromakalim-induced relaxation in the ring with or without naloxone in a dose-dependent manner. The magnitude of the R(-)-tramadol-induced attenuation of vasorelaxant response induced by levcromakalim was greater (P < 0.05) than that induced by S(+)-tramadol. Glibenclamide almost abolished the levcromakalim-induced relaxation. Tramadol, 5 × 10 -5 M, did not significantly alter the diltiazem-induced relaxation. Conclusion: These results suggest that a supraclinical dose (10 -5 M) of tramadol [racemic, R(-) and S(+)] attenuates the vasorelaxation mediated by the K ATP channels in the rat aorta. The R(-) tramadol-induced attenuation of vasorelaxation induced by levcromaklim was more potent than that induced by S(+) tramadol. This attenuation is independent of opioid receptor activation. Méthode : Les effets du tramadol (racémique, R(-) et S(+) : 10 -6 , 10 -5 , 5 × 10 -5 M), et du glibenclamide sur la courbe dose-réponse du levcromakalim ont été évalués sur des anneaux aortiques pré-contractés avec de la phényléphrine. Sur les anneaux indépendam-ment prétraités au naloxone et au glibenclamide, les courbes de dose-réponse du levcromakalim ont été générées en présence ou en l'absence de tramadol. L'effet du tramadol sur la courbe doseréponse du diltiazem a été évalué. Résultat : Le tramadol racémique R(-) et S(+) a atténué (P <

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Section: Discussionsupporting

confidence: 68%

Inhibitory effect of tramadol on vasorelaxation mediated by ATP-sensitive K+ channels in rat aorta

Cho

Sohn

Park³

et al. 2007

Can J Anesth/J Can Anesth

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“…Whether or not direct cardiac toxicity can be caused by high doses tramadol is unclear. There are no published human reports but experimental studies have reported that high doses of tramadol (bolus injections of 5 to 10 mg/kg) significantly decreased cardiac contractility (21)(22) or caused cardiac depression (23). Moreover, it was reported that the tissue distribution of tramadol was not different between the peripheral blood (14) calculated within the first 24 hours of ICU admission are used to predict the risk of death.…”

Section: Discussionmentioning

confidence: 99%

Refractory shock and asystole related to tramadol overdose

Daubin

Quentin

Goullé

et al. 2007

Clinical Toxicology

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Introduction. Tramadol use is largely considered safe. However, several lethal cases of tramadol intoxication were reported, suggesting an underestimated toxicity. We report for a tramadol overdose case in combination with other central nervous system depressants, leading to refractory shock requiring extracorporeal life support. Case report. A 33-year-old man was admitted in our intensive care unit for drug intoxication with coma, seizures, and hypotension without signs of heart failure. A few hours later, he developed a ventricular tachycardia, followed by a brief cardiac arrest in asystole with refractory shock requiring an extracorporeal life support, vasopressors, and hemofiltration. With this aggressive support, his overall status gradually improved. Repeated echocardiography showed an improvement in the cardiac function. The patient was weaned off extracorporeal life support on day eight and discharged on day 12. On admission, a urine analysis, using gas chromatography-mass spectrometry, showed high peaks of tramadol and desmethyltramadol with the presence of hydroxyzine, gabapentine, and clonazepam. The tramadol blood concentration measured by the high-performance liquid chromatography method-diode array detector was 23.9 mg/L, much higher than many previously reported fatal overdoses. No other drugs with potential cardiac toxicity, such as beta-blockers, calcium antagonists, antiarrythmic, antidepressants, meprobamate, or other xenobiotics were detected. Conclusion. This case illustrates that tramadol overdose may cause refractory shock and asystole when taken in combination with CNS depressants, and reminds all physicians to be vigilant with regard to the potential toxic effects of tramadol.

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“…Some analgesic agents have also revealed relaxant effects in smooth muscle (9,10). (+)-tramadol was found to activate peripheral opioid µ-receptors to exhibit a concentration-dependent relaxation of aorta (11). Basically, the opioid µ-receptors have been divided into 3 subtypes, including µ-1, µ-2 and µ-3 opioid receptors (12).…”

Section: Introductionmentioning

confidence: 99%

Prostatic relaxation induced by loperamide is mediated through activation of opioid μ-2 receptors in vitro

Lu¹,

Chung²

2011

Experimental and Therapeutic Medicine

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Abstract. the merit of opioid µ-receptor activation in the improvement of benign prostatic hyperplasia (Bph) remains obscure. in the present study, we used loperamide to identify the subtype of opioid µ-receptors involved in prostatic relaxation and investigate the possible mechanism of this relaxation. prostate strips were isolated from 12-week-old male Wistar rats for identification of isometric tension. The prostate strips were precontracted with either 1 µmol/l phenylephrine or 50 mmol/l Kcl. the decrease in muscle tone (relaxation) was then characterized after cumulative administration of loperamide (0.1 to 10 µmol/l) into the organ bath for the concentration-dependent study. Pretreatment with specific blockers or antagonists was carried out to compare the changes in loperamide-induced relaxation. loperamide produced a marked relaxation in the isolated prostates precontracted with phenylephrine or Kcl in a dose-dependent manner. this relaxation was abolished by cyprodime, a selective opioid µ-receptor antagonist, but was not modified by naloxonazine at a dose sufficient to block the opioid µ-1 receptors. treatment with an agonist for opioid µ-1 receptors also failed to modify the muscle tone. moreover, the relaxation by loperamide was attenuated by glibenclamide at a dose sufficient to block ATP-sensitive K + channels. in addition, this action of loperamide was abolished by protein kinase a (pKa) inhibitor and enhanced by the inhibitor of phosphodiesterase for cyclic amp (camp). Our results suggest that loperamide induces prostatic relaxation through activation of opioid µ-2 receptors via the camp-pKa pathway to open atp-sensitive K + channels. IntroductionBenign prostatic hyperplasia (Bph) occurs frequently in older men and is associated with lower urinary tract symptoms causing obstruction of the proximal urethra and urinary flow disturbances (1). In clinics, medical treatments for BPH include widely used α-1 antagonists and 5-α-reductase inhibitors. however, the side effects, such as postural hypotension, erectile dysfunction and ejaculatory difficulty, disturb the quality of life of these patients (2,3). therefore, development of a more effective therapy for the treatment of Bph is urgent and necessary.loperamide is widely used in the clinic for a variety of diarrheal syndromes, including acute and nonspecific (infectious) diarrhea (4,5). Recently, we identified opioid µ-receptor expression in rat prostates, and prostatic relaxation was induced by the activation of opioid µ-receptors using loperamide (6). loperamide was introduced as a peripheral agonist of opioid µ-receptors with poor ability to penetrate the bloodbrain barrier (7,8). Some analgesic agents have also revealed relaxant effects in smooth muscle (9,10). (+)-tramadol was found to activate peripheral opioid µ-receptors to exhibit a concentration-dependent relaxation of aorta (11). Basically, the opioid µ-receptors have been divided into 3 subtypes, including µ-1, µ-2 and µ-3 opioid receptors (12). however, activation of opioid µ-1 receptors ...

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In vitro and in vivo vasodilator activity of racemic tramadol and its enantiomers in Wistar rats

Cited by 37 publications

References 16 publications

Inhibitory effect of tramadol on vasorelaxation mediated by ATP-sensitive K+ channels in rat aorta

Inhibitory effect of tramadol on vasorelaxation mediated by ATP-sensitive K+ channels in rat aorta

Refractory shock and asystole related to tramadol overdose

Prostatic relaxation induced by loperamide is mediated through activation of opioid μ-2 receptors in vitro

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