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

Tramadol ((±)-tramadol) is an analgesic agent formulated as a racemic mixture (1 : 1) of (−)- and (+)-tramadol, which differ in their potency to bind to μ-opioid receptors and to inhibit monoamine-reuptake. We investigated the stereoselectivity of in vitro tramadol-induced vasodilatation of aortic rings and its effect on the arterial blood pressure measured in conscious Wistar rats. (+)-Tramadol, but not (−)-tramadol, produced a concentration-dependent relaxation of aorta precontracted with phenylephrine. The concentration–response curve was significantly altered by the removal of endothelium. Vascular relaxation was also inhibited by pre-incubation of endothelium-intact aorta with naloxone, suggesting the involvement of opioid receptors. The vasodilatation produced by tramadol was stereoselective, and the (+)-tramadol-induced vasodilatation was mediated by μ-opioid receptors and partially dependent on endothelium integrity. The hypotensive response induced by (+)-tramadol was also observed after bolus injection of 5.0 and 10.0 mg/kg. The results indicate that only high doses of tramadol cause cardiac depression and hypotension, indicating that it can be used safely.