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ANESTHETIC PHARMACOLOGY

A Supraclinical Dose of Tramadol Stereoselectively Attenuates Endothelium-Dependent Relaxation in Isolated Rat Aorta

Il-Woo Shin, MD^*, Ju-Tae Sohn, MD^*, Kyeong-Eon Park, MD^*, Ki Churl Chang, PhD, Ju-Young Choi, MD^*, Heon-Keun Lee, MD^*, and Young-Kyun Chung, MD^*

From the *Department of Anesthesia and Pain Medicine, Gyeongsang National University College of Medicine; Institutes of Health Sciences, Gyeongsang National University; and Department of Pharmacology, Gyeongsang National University College of Medicine, Gyeongnam, Republic of Korea.

Address correspondence and reprint requests to Ju-Tae Sohn, MD, Department of Anesthesia and Pain Medicine, Gyeongsang National University Hospital, 90 Chilam-dong, Jinju, Gyeongnam, 660-702, Republic of Korea. Address e-mail to jtsohn{at}nongae.gsnu.ac.kr.

Tramadol, a combination of R(–) and S(+) enantiomers, inhibits both the acetylcholine-mediated response of muscarinic receptors and the muscarine-induced accumulation of cyclic guanosine monophosphate. Our goals in this in vitro study were to investigate the effects of tramadol on endothelium-dependent relaxation induced by acetylcholine, to determine whether this effect of tramadol is stereoselective, and to elucidate the associated cellular mechanism in rat aorta. In endothelium-intact rings precontracted with phenylephrine with or without naloxone, dose-response curves for acetylcholine, histamine, and calcium ionophore A23187 were generated in the presence and absence of tramadol (racemic, R(–) and S(+)). Sodium nitroprusside dose-response curves were generated in the presence and absence of racemic tramadol. Racemic tramadol (5 x 10^–5 10^–4 M) attenuated acetylcholine-induced relaxation in the rings with or without naloxone. R(–) tramadol, 5 x 10^–5 M, attenuated acetylcholine-induced relaxation, whereas S(+) tramadol, 5 x 10^–5 M, did not. Racemic tramadol (10^–4 M) had no effect on dose-response curves for calcium ionophore A23187 or sodium nitroprusside. Taken together, these results indicate that tramadol, at a supraclinical dose (5 x 10^–5 M), stereoselectively attenuates endothelium-dependent relaxation via an inhibitory effect at levels proximal to nitric oxide synthase activation on a pathway involving nonspecific endothelial receptor activation.