Anesth Analg 2006;103:366-371
© 2006 International Anesthesia Research Society
doi: 10.1213/01.ane.0000225913.64876.d2
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.
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Abstract
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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.
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Introduction
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Endothelial cells contribute to the local regulation of vasomotor tone by releasing dilator and constrictor substances. The vascular endothelium releases endothelium-derived relaxing factor (1), which relaxes vascular smooth muscle by the formation of 3',5'–cyclic guanosine monophosphate (cGMP) through activation of guanylate cyclase (2). IV anesthetics (thiopental, ketamine, propofol, midazolam, etomidate) (3–5) and fentanyl (6) attenuate vascular nitric oxide (NO)-cGMP system-mediated relaxation after acetylcholine stimulation.
Tramadol hydrochloride, a combination of S(+) and R(–) enantiomers, produces its analgesic effect in humans by weak affinity for µ-opioid receptors and inhibition of norepinephrine and serotonin reuptake (7). S(+) tramadol is a more potent agonist of the µ-opioid receptor and a more potent inhibitor of serotonin reuptake, whereas R(–) tramadol is a more potent inhibitor of norepinephrine reuptake (7), suggesting that tramadol enantiomers have stereoselective analgesic effects. Tramadol inhibits both the acetylcholine-mediated response of M1 and M3 muscarinic receptors expressed in Xenopus oocytes and the muscarine-induced cGMP accumulation (8,9). We previously reported that the endothelial M3 muscarinic receptor is functionally important in mediating acetylcholine-induced relaxation in rat aorta (6). However, to our knowledge, the effects of tramadol on endothelium-dependent relaxation induced by the muscarinic receptor agonist, acetylcholine, in rat aorta have not been investigated. Therefore, the goals of 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. Based on previous studies (6,8,9), we tested the hypothesis that tramadol would attenuate the endothelium-dependent relaxation in isolated rat aorta.
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METHODS
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All the experimental procedures and protocols were approved by the Institutional Animal Care and Use Committee of Gyeongsang National University Hospital (Jinju, Gyeongnam, Republic of Korea).
Male Sprague-Dawley rats weighing 250–350 g were anesthetized with IP pentobarbital sodium (50 mg/kg). The descending thoracic aorta was dissected free, and the surrounding connective tissue and fat were removed under a microscope while the vessel was bathed in Krebs solution of the following composition (mM): 118 NaCl, 4.7 KCl, 1.2 MgSO4, 1.2 KH2PO4, 2.4 CaCl2, 25 NaHCO3, 11 glucose, and 0.03 EDTA. The aorta was then cut into 2.5- to 3-mm rings, which were suspended on Grass isometric transducers (FT-03; Grass Instruments, Quincy, MA) at 2.0 g resting tension in 10 mL temperature-controlled baths (37°C) containing Krebs solution continuously gassed with 95% O2 and 5% CO2. The rings were equilibrated at 2.0 g resting tension for 120 min, during which time the bathing solution was changed every 15 min. Care was taken not to damage the endothelium. In some aortic rings, the endothelium was intentionally removed by inserting a 25-gauge needle tip into the lumen of the ring and gently rolling the ring for a few seconds. The contractile response induced by phenylephrine (10–7 M) was measured in all aortic rings. Once the phenylephrine (10–7 M)-induced contraction had stabilized, acetylcholine (10–6 M) was added to assess the integrity of the endothelium. The endothelial integrity was confirmed by an observation of >80% relaxation by acetylcholine (10–6 M). Rings were then rinsed five times with Krebs solution to restore tension to the precontracted level. Only one concentration-response curve elicited by endothelium-dependent relaxing drugs (acetylcholine, histamine, and calcium ionophore A23187) or endothelium-independent relaxing drug (sodium nitroprusside) was made from each ring.
The first series of this in vitro experiment was conducted to assess the effect of racemic tramadol on endothelium-dependent relaxation evoked by endothelial receptor activators (acetylcholine and histamine). The racemic tramadol was added directly to the organ bath 20 min before phenylephrine (10–6 M)-induced contraction. Rings were precontracted with 10–6 M phenylephrine. When the contractile response stabilized, incremental concentrations of acetylcholine (10–9 to 10–5 M) and histamine (10–8 to 10–4 M) were added to the organ bath to generate a concentration-response curve in the endothelium-intact rings. The effect of racemic tramadol (10–6, 5 x 10–5, 10–4 M) on the concentration-response curves for acetylcholine and histamine was assessed by comparing the vasorelaxant response in the presence and absence of racemic tramadol.
The second series of experiments was designed to determine whether racemic tramadol-induced attenuation of endothelium-dependent relaxation evoked by acetylcholine was stereoselective. The incubation period for R(–) tramadol or S(+) tramadol was 20 min before phenylephrine (10–6 M)-induced contraction. The effect of tramadol enantiomers (R(–) tramadol: 5 x 10–5, 10–4 M; S(+) tramadol: 5 x 10–5, 10–4 M) on the concentration-response curve for acetylcholine was assessed by comparing each vasorelaxant response in the presence and absence of R(–) or S(+) tramadol.
In the third series of experiments, the effect of 10–4 M racemic tramadol on the concentration-response curve for calcium ionophore A23187 (10–9 to 3 x 10–7 M) was assessed by comparing the vasorelaxant response in the presence and absence of 10–4 M racemic tramadol. The racemic tramadol was added directly to the organ bath 20 min before phenylephrine (10–6 M)-induced contraction.
In the fourth series of experiments, the effect of 10–4 M racemic tramadol on the concentration-response curve for the endothelium-independent NO donor, sodium nitroprusside (SNP: 10–9 to 10–6 M) in endothelium-denuded rings was assessed by comparing the vasorelaxant response in the presence and absence of 10–4 M tramadol. The racemic tramadol was added directly to the organ bath 20 min before phenylephrine (10–6 M)-induced contraction.
Finally, to investigate the participation of opioid receptors in racemic tramadol-induced attenuation of endothelium-dependent relaxation induced by acetylcholine, the acetylcholine concentration-response curve was assessed after the nonspecific opioid receptor antagonist, naloxone (10–6 M), was added directly to the organ bath, either alone or after combined pretreatment with racemic tramadol (5 x 10–5, 10–4 M). The incubation period for naloxone alone or naloxone plus racemic tramadol was 20 min before phenylephrine (10–6 M)-induced contraction.
All drugs were of the highest purity commercially available: phenylephrine HCl, acetylcholine, histamine, calcium ionophore A23187, naloxone, sodium nitroprusside (Sigma Chemical, St. Louis, MO), and racemic tramadol (Yuhan CO, Seoul, Republic of Korea). R(–) tramadol and S(+) tramadol were a kind gift from Grünenthal GmbH (Germany). All concentrations are expressed as the final molar concentration in the organ bath. Calcium ionophore A23187 was initially dissolved in dimethyl sulfoxide (0.05% volume/volume) (3) and subsequently diluted in distilled water. Unless stated otherwise, all other drugs were dissolved and diluted in distilled water.
Values are expressed as mean ± sd. Vasorelaxant responses to acetylcholine, histamine, calcium ionophore A23187, and sodium nitroprusside are expressed as the percentage relaxation of the precontraction induced by 10–6 M phenylephrine. The logarithm of drug concentration producing 50% of the maximum relaxation response (ED50) was calculated by nonlinear regression analysis by fitting the dose-response relationship for each vasorelaxant to a sigmoidal curve using commercially available software (Prism version 3.02; GraphPad Software, San Diego, CA). The data were fitted to a sigmoid dose-response curve using the following algorithm: Y = Bottom + (Top – Bottom)/(1 + 10
((LogED50 – X) x Hill Slope)). The concentration ratio was calculated as the ratio of the ED50 for acetylcholine in the presence and absence of tramadol enantiomers, and used for comparing the magnitude of tramadol enantiomer (R(–) and S(+) tramadol)-induced attenuation of endothelium-dependent relaxation evoked by acetylcholine. The maximum relaxant response (Rmax) was measured as the maximal response to each vasorelaxant, with Rmax = 100% indicating complete reversal of phenylephrine (10–6 M)-induced contraction. Statistical analysis was performed using Student’s t-test for paired samples, or one-way analysis of variance followed by the Tukey multiple comparison. Differences were considered statistically significant at P < 0.05. N refers to the number of rats whose descending thoracic aortic rings were used in each protocol. Each group contained at least two rings from the same rat.
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RESULTS
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Tramadol, 10–6 M, did not significantly alter the acetylcholine concentration-response curve. However, large doses (5 x 10–5, 10–4 M) of tramadol significantly attenuated (P < 0.05) the endothelium-dependent relaxation evoked by acetylcholine (ED50; no drug: –7.30 ± 0.19, 5 x 10–5 M tramadol: –6.95 ± 0.15, 10–4 M tramadol: –6.84 ± 0.09) and histamine (ED50; no drug: –5.84 ± 0.32 versus 10–4 M tramadol: –5.36 ± 0.22) (Fig. 1, Fig. 2).
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Figure 1. Effect of tramadol on acetylcholine dose-response curve. Tramadol (10–6 M) had no effect on acetylcholine dose-response curve. Large-dose (5 x 10–5, 10–4 M) tramadol produced a significant rightward shift in the acetylcholine dose-response curve (*P < 0.01 versus no drug; P < 0.05 versus 10–6 M tramadol). Data are shown as mean ± sd and are expressed as the percentage relaxation of precontraction induced by 10–6 M phenylephrine (precontraction induced by 10–6 M phenylephrine: 100% = 1.84 ± 0.56 g [n = 18], 100% = 1.78 ± 0.81 g [n = 5], 100% = 2.26 ± 0.55 g [n = 7] and 100% = 2.16 ± 0.45 g [n = 11] for the rings not treated with tramadol, the tramadol [10–6 M], [5 x 10–5 M] and [10–4 M] pretreated rings, respectively).
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Figure 2. Effect of tramadol on histamine dose-response curve. Tramadol (10–4 M) produced a significant rightward shift (*P < 0.05 versus no drug) in the histamine dose-response curve, and attenuated the histamine-induced maximal relaxation (#P < 0.05 versus no drug). Data are shown as mean ± sd and are expressed as the percentage relaxation of precontraction induced by 10–6 M phenylephrine (precontraction induced by 10–6 M phenylephrine: 100% = 1.93 ± 0.53 g [n = 5] and 100% = 2.22 ± 0.79 g [n = 5] for the rings not treated with tramadol and the tramadol [10–4 M] pretreated rings, respectively).
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R(–) and S(+) tramadol (10–4 M) attenuated (P < 0.05) acetylcholine-induced relaxation (ED50; no drug: –7.25 ± 0.24 versus 10–4 M R(–) tramadol: –6.69 ± 0.13, no drug: –7.16 ± 0.20 versus 10–4 M S(+) tramadol: –6.94 ± 0.17) (Fig. 3A, 3B). S(+) tramadol, 5 x 10–5 M, had no effect on acetylcholine-induced relaxation, whereas R(–) tramadol, 5 x 10–5 M, attenuated (P < 0.05) acetylcholine-induced relaxation (ED50; no drug: –7.25 ± 0.24 versus 5 x 10–5 M R(–) tramadol: –6.94 ± 0.18) (Fig. 3A, 3B). In addition, the magnitude of tramadol enantiomers (10–4 M)-induced attenuation of vasorelaxation evoked by acetylcholine was greater (P < 0.05) in the rings pretreated with 10–4 M R(–) tramadol than 10–4 M S(+) tramadol (concentration ratio 10–4 M R(–) tramadol: 4.18 ± 1.54 versus 10–4 M S(+) tramadol: 1.80 ± 0.50) (Fig. 3A, 3B).
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Figure 3. A, Effect of R(–) tramadol on acetylcholine dose-response curve. R(–) tramadol (5 x 10–5, 10–4 M) produced a significant rightward shift (*P < 0.05 versus no drug) in the acetylcholine dose-response curve. Data are shown as mean ± sd and are expressed as the percentage relaxation of precontraction induced by 10–6 M phenylephrine (precontraction induced by 10–6 M phenylephrine: 100% = 2.20 ± 0.25 g [n = 7], 100% = 2.42 ± 0.29 g [n = 7] and 100% = 2.37 ± 0.34 g [n = 7] for the rings not treated with tramadol, the tramadol [5 x 10–5 M] and [10–4 M] pretreated rings, respectively). B, Effect of S(+) tramadol on acetylcholine dose-response curve. S(+) tramadol, 5 x 10–5 M, had no effect on acetylcholine dose-response curve, whereas S(+) tramadol, 10–4 M, produced a significant rightward shift (*P < 0.05 versus no drug) in the acetylcholine dose-response curve. Data are shown as mean ± sd, and are expressed as the percentage relaxation of precontraction induced by 10–6 M phenylephrine (precontraction induced by 10–6 M phenylephrine: 100% = 1.98 ± 0.56 g [n = 16], 100% = 1.95 ± 0.44 g [n = 6] and 100% = 2.06 ± 0.36 g [n = 13] for the rings not treated with tramadol, the tramadol [5 x 10–5 M] and [10–4 M] pretreated rings, respectively).
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Tramadol, 10–4 M, did not significantly alter calcium ionophore A23187-induced relaxation (ED50; no drug: –7.12 ± 0.22 versus 10–4 M tramadol: –7.00 ± 0.17) (Fig. 4).
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Figure 4. Effect of tramadol on the calcium ionophore A23187 dose-response curve. Tramadol, 10–4 M, did not significantly alter the calcium ionophore A23187 dose-response curve. Data are shown as mean ± sd and are expressed as the percentage relaxation of precontraction induced by 10–6 M phenylephrine (precontraction induced by 10–6 M phenylephrine: 100% = 3.01 ± 0.65 g [n = 8] and 100% = 3.26 ± 0.68 g [n = 8] for the rings not treated with tramadol and the tramadol [10–4 M] pretreated rings, respectively).
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Tramadol, 10–4 M, had no effect on SNP-induced relaxation in the endothelium-denuded rings (ED50; no drug: –7.39 ± 0.202 versus 10–4 M tramadol: –7.45 ± 0.19) (Fig. 5).
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Figure 5. Effect of tramadol on the sodium nitroprusside dose-response curve in endothelium-denuded rings. Tramadol, 10–4 M, did not significantly alter the sodium nitroprusside dose-response curve. Data are shown as mean ± sd, and are expressed as the percentage relaxation of precontraction induced by 10–6 M phenylephrine (precontraction induced by 10–6 M phenylephrine: 100% = 3.12 ± 0.41 g [n = 6] and 100% = 3.14 ± 0.28 g [n = 6] for the rings not treated with tramadol, and the tramadol [10–4 M] pretreated rings, respectively).
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Tramadol (5 x 10–5, 10–4 M) significantly attenuated (P < 0.05) the endothelium-dependent relaxation evoked by acetylcholine in rings pretreated with 10–6 M naloxone (ED50; no drug: –7.25 ± 0.27, 5 x 10–5 M tramadol: –6.94 ± 0.14, 10–4 M tramadol: –6.80 ± 0.23) (Fig. 6).
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Figure 6. Effect of tramadol on acetylcholine dose-response curve in rings pretreated with 10–6 M naloxone. Tramadol (5 x 10–5 10–4 M) produced a significant rightward shift (*P < 0.05 versus no drug) in the acetylcholine dose-response curve. Data are shown as mean ± sd and are expressed as the percentage relaxation of precontraction induced by 10–6 M phenylephrine (precontraction induced by 10–6 M phenylephrine: 100% = 1.88 ± 0.26 g [n = 7], 100% = 1.85 ± 0.32 g [n = 7] and 100% = 2.04 ± 0.30 g [n = 7] for the rings not treated with tramadol, the tramadol [5 x 10–5 M] and [10–4 M] pretreated rings, respectively).
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DISCUSSION
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This is the first study demonstrating that in isolated rat aorta, 5 x 10–5 M racemic and R(–) tramadol attenuated endothelium-dependent relaxation induced by acetylcholine, whereas 5 x 10–5 M S(+) tramadol did not affect this relaxation. These results indicate that tramadol, at a supraclincial dose (5 x 10–5 M), stereoselectively attenuates acetylcholine-induced relaxation via an inhibitory effect at a site distal to endothelial receptor activation but proximal to NO synthase (NOS) activation, in rat aorta. This attenuation is independent of opioid receptor activation, and not specific to endothelial muscarinic receptor activation.
Tramadol (5 x 10–5, 10–4 M) at a supraclinical concentration significantly attenuated acetylcholine-induced relaxation, whereas 10–6 M tramadol (10), which is the peak serum concentration after oral administration of 100 mg tramadol, had no effect on this relaxation. The peak plasma tramadol concentration increases in elderly healthy patients and patients with hepatic impairment or renal insufficiency (11). Because 20% of tramadol is bound to plasma protein (11), changes in the amount or binding capacity of protein in certain pathologic conditions (e.g., liver disease, hemodilution, hypoproteinemia) could result in an increase in the free fraction of tramadol. Considering the above factors, 5 x 10–5 M tramadol may be a concentration found in clinical settings, such as during an overdose of tramadol or severe hepatic and renal dysfunction.
Tramadol inhibits acetylcholine-mediated response of M1 (8) and M3 (9) muscarinic receptors expressed in Xenopus laevis oocytes. O-desmethyl tramadol (M1), which is one of main metabolites of tramadol, inhibits the acetylcholine-mediated response of M1 muscarinic receptor (12). Previous studies (8,9,12) suggest that tramadol inhibits muscarinic receptor function by interacting with acetylcholine binding sites. In rat aorta, acetylcholine-induced relaxation is mediated primarily by endothelial M3 muscarinic receptor activation (6). Racemic tramadol (5 x 10–5, 10–4 M) attenuated endothelium-dependent relaxation induced by acetylcholine and histamine. Taken together, these results indicate that tramadol-induced attenuation of vasorelaxation induced by endothelial receptor activators is not specific to endothelial muscarinic receptor activation. The fact that tramadol attenuated acetylcholine-induced relaxation in rings pretreated with 10–6 M naloxone suggests that the tramadol-induced attenuation is caused by a direct action on the pathway for acetylcholine-induced relaxation. Both R(–) and S(+) enantiomers of tramadol contribute to analgesic activity, but via different mechanisms (7). S(+) tramadol and the metabolite (+)-O-desmethyl-tramadol (M1) are agonists of the µ-opioid receptor (7). S(+) tramadol is approximately 66-fold more potent than R(–) tramadol at inhibition of serotonine reuptake, whereas R(–) tramadol is approximately 120-fold more potent than S(+) tramadol at inhibition of norepinephrine reuptake, enhancing the inhibitory effect on pain transmission in the spinal cord (7). The potency of racemic tramadol is between the two enantiomers at each site (7). In accordance with previous stereoselectivity studies (7,13), the magnitude of tramadol enantiomers (10–4 M)-induced attenuation of vasorelaxation evoked by acetylcholine was more potent in the rings pretreated with 10–4 M R(–) tramadol than 10–4 M S(+) tramadol. Taken together, these results indicate that tramadol stereoselectively attenuates acetylcholine-induced relaxation.
Regardless of the type of stimulus, an increase in intracellular free calcium ([Ca2+]i) is a prerequisite for an increase in endothelial NOS (14). Calcium ionophore A23187 increases [Ca2+]i both by increasing the calcium permeability of the cell membrane and promoting calcium release from the sarcoplasmic reticulum (15) and can therefore activate NOS. In accordance with a previous study (16), tramadol did not alter the calcium ionophore A23187 dose-response curve. Taken together, these results suggest that the possible site for tramadol to interfere with acetylcholine-induced relaxation is proximal to NOS activation. Because the vasorelaxant response to SNP was not attenuated by 10–4 M tramadol, it is unlikely that tramadol causes attenuation by inhibiting NO function. Further study of the influence of tramadol on endothelial receptor activators binding is needed to elucidate the detailed mechanism.
Bolus administration (2 mg/kg) of tramadol causes a transient increase in arterial blood pressure with a concomitant increase of serum norepinephrine (17). In isolated guinea pig atria and papillary muscle, tramadol (10–6 to 10–4 M) shows a concentration-dependent positive inotropic effect (18). Large doses of tramadol produce vasodilation by NO production and by a direct effect on smooth muscle (19). Thus, the net hemodynamic effects of tramadol in vivo are a composite of vascular, myocardial, and neural effects. Any clinical implication of tramadol on regional hemodynamics must be tempered by the fact that a large conduit artery, the aorta, was used in this in vitro experiment, whereas the resistance vessels with a diameter of 100–300 µm control most organ blood flow (20). Proceeding from the larger to smaller arteries and arterioles, the relative importance of endothelium-derived hyperpolarizing factors in the control of blood flow increases, while that of NO decreases (21). However, agonist-mediated release of NO acts as a reserve to satisfy a transient, local requirement for large concentrations of NO (14). Even with these limitations (20,21), our finding may help provide a pharmacological basis for understanding the interaction of tramadol with vascular NO-cGMP system under acetylcholine stimulation.
In conclusion, these results indicate that tramadol, at a supraclinical concentration, stereoselectively attenuates endothelium-dependent relaxation via an inhibitory effect at levels proximal to NOS activation on a pathway involving nonspecific endothelial receptor activation in rat aorta. This attenuation does not occur through opioid receptor activation.
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ACKNOWLEDGMENT
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The authors wish to thank Jae Soo Suh at the Yuhan Cooperation (Seoul, Republic of Korea) for the donation of R(–) and S(+) tramadol from Grünenthal GmbH (Germany).
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Footnotes
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Accepted for publication April 4, 2006.
Supported, in part, by a research grant from Gyeongsang National University Hospital.
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Abstract
Introduction
