Surgical procedures can now be performed more safely in patients with organ failure, such as chronic renal insufficiency, thanks to recent developments in intensive care treatment (1,2). Nonsteroidal antiinflammatory drugs (NSAIDs) are, however, still used as analgesics for postoperative pain relief, although they often cause renal dysfunction (3,4). Ideally, postoperative analgesics that have protective effects on renal function should be used in such conditions, but such a model analgesic has not yet been identified.
Tramadol, an analgesic, is often used to control acute and chronic pain. Several investigators have reported that tramadol inhibits reuptake of norepinephrine (NE) released from nerve endings due to inhibiting the NE transporter function and that the regulation of NE concentration is one of the mechanisms underlying its analgesic effect (5,6). In the perioperative period, sympathetic nerve activation induces renal hypoperfusion, potentially leading to serious renal complications, particularly in older patients with renal insufficiency (7–9). In addition, whereas serum NE levels are increased during surgery, renal blood flow (RBF) is reduced secondary to NE-induced vasoconstriction of the renal arteries. These results suggest that tramadol might affect renal hemodynamics by changing the activity of sympathetic nerves through modulation of NE. The effect of tramadol on renal hemodynamics in vivo, however, has not been well elucidated.
This study, therefore, investigated the effects of tramadol on cortical RBF, mean arterial blood pressure (MAP), and heart rate (HR) in normal anesthetized rats. We also examined the effects of tramadol on RBF in rats with nephritis induced experimentally by anti-Thy 1.1 antibody administration.
Drugs were obtained from the following sources: tramadol from Nippon Shinyaku (Kyoto, Japan), monoclonal antibody OX-7 against Thy 1.1 from Cosmo Bio (Tokyo, Japan), lactated Ringer’s solution from Otsuka (Tokyo, Japan), and NE from Sigma (St. Louis, MO). This study conformed to the Guide for the Care and Use of Laboratory Animals adopted and promulgated by the Japanese National Institute of Health, and approval was granted by the Animal Research Committees of the University of Occupational and Environmental Health.
The procedure for measuring arterial blood pressure has been reported previously (10,11). Briefly, adult male Wistar rats (300-g body weight) were anesthetized by intraperitoneal injection of pentobarbital sodium (50 mg/kg). After an animal was placed in a restraining cage, a polyvinyl chloride catheter was inserted into the tail vein to deliver IV solutions. Another catheter was placed in the femoral artery to measure MAP. Throughout the experiments, MAP was measured with a calibrated pressure transducer (Baxter Healthcare, Santa Ana, CA) positioned one-third of the distance from the brisket to the top of the back, and it was recorded with a polygraph (Datascope870 monitor; Datascope Corporation, Paramus, NJ) and the MacLab/2 data acquisition system (AD Instruments Pty. Ltd., Castle Hill, New South Wales, Australia). To measure cortical RBF continuously, we used a laser Doppler flowmeter positioned in the outermost layer of the kidney (11). The flank was incised to expose the left kidney, and the probe of a laser Doppler flowmeter (BRC-100; Bioresearch Center, Nagoya, Japan) was fixed to the surface of the kidney. RBF was recorded with a MacLab/2 data acquisition system. The animals were allowed at least 60 min to equilibrate after surgical preparation to eliminate the effects of surgical stimulation. To delete intraobserver variability, the same investigators performed the surgery and measurements in all experiments. The anesthesia by intraperitoneal injection of pentobarbital sodium was stable during the experiments; oxygen was supplied, and body temperature was maintained at 37°C with a heating pad. We documented that no change in pH, blood gas indices, electrolytes, or hematocrit occurred throughout the experiment (data not shown).
The experiments were performed as follows: After an equilibration period of 60 min, continuous mea-surement of MAP, HR, and RBF commenced. Tramadol was injected into the tail vein for 10 s by using an infusion pump (SP-500; JMS, Hiroshima, Japan). RBF, HR, and MAP were measured 2 min before injection of tramadol as a control, and then a bolus injection of the tramadol was administered to compare the maximal effect by the tramadol administration with control. Maximal changes in MAP, HR, and RBF were observed within approximately 5 min of the administration of tramadol. Tramadol was administered (1, 2, 3, 4, 5, and 6 mg/kg) in order of dosage. After an interval of at least 40 min after one dose, the next dose was administered in sequence.
Serum NE concentration was also measured before and after tramadol injection (2 mg/kg) in normal anesthetized rats (n = 6), as previously reported in our laboratory (12). Blood samples were collected before and after a bolus injection of tramadol. These were centrifuged at 1500 g for 5 min at 4°C. Serum was stored at −80°C until the NE assay. Serum NE was adsorbed onto activated Al2O3 and separated by high-performance liquid chromatography (LC-5A; Shimadzu, Kyoto, Japan) by using a reverse-phase C18 (2.6 × 250 mm) Cosmosil column (Nacalai Tesque, Kyoto, Japan). The extracted NE was assayed by electrochemical detection by using an amperometer (S875; Irica, Kyoto, Japan). The working electrode potential was +0.7 V compared with the Ag/AgCl reference electrode. Serum NE was not lost during this measurement, and NE recovery from NE in serum with this procedure was approximately 99%.
The experiments to study the effects of continuous IV administration of tramadol on MAP, HR, and RBF were performed as follows. After a 60-min equilibration period after surgery, MAP, HR, and RBF values were recorded as control. Then, continuous IV administration of tramadol was started at 0.5 mg · kg−1 · h−1. Thirty minutes after 0.5 mg · kg−1 · h−1 tramadol was started, HR, RBF, and MAP were measured. Thereafter, the doses were increased by 0.5 or 1 mg · kg−1 · h−1 every 40 min (0.5–4 mg · kg−1 · h−1). Likewise, 30 min after each dose was started, HR, MAP, and RBF were measured.
Anti-Thy 1.1 was used to induce nephritis in rats by bolus IV injection of 1 mg/kg OX-7, a monoclonal antibody targeted against Thy 1.1, the mesangial cell membrane antigen (13). Because the administration of antibody reduces RBF, blood urea nitrogen (BUN) and creatinine (Cr) were measured 30 h after antibody administration. These indicators of renal function were compared with those of normal rats, and only rats with clear renal dysfunction (as assessed by the BUN and Cr) were used for further experiments (see Results). The experiments were performed in the following manner: After an equilibration period of 60 min after surgery, measurement of MAP, HR, and RBF commenced. Tramadol was injected into the tail vein for 10 s by using the infusion pump. RBF, HR, and MAP were recorded 2 min before the addition of tramadol as a control, and then a bolus injection of tramadol was administered to compare the maximal effect by the tramadol administration with control. Maximal changes in MAP, HR, and RBF were observed within approximately 5 min of the administration of tramadol. Tramadol was administered (1, 2, 3, 4, and 6 mg/kg) in order of dosage. After an interval of at least 40 min after one dose, the next dose was administered in sequence.
Because of the variability between rats, the results are expressed as a percentage of control values. MAP is expressed in millimeters of mercury, and RBF is expressed in millivolts in accordance with previous reports that used the same laser Doppler flowmeter to measure RBF (10,11). All values are expressed as the mean ± sd. Statistical evaluation consisted of a one-way analysis of variance followed by a post hoc test (Duncan’s multiple range test). A value of P < 0.05 was considered to be statistically significant.
We examined the effects of a bolus injection of tramadol (1–6 mg/kg, n = 12) on MAP, HR, and RBF. In our preliminary experiment, injection of lactated Ringer’s solution alone did not alter MAP (99.2% ± 0.5% of control, n = 5, not significant), HR (98.3% ± 3.0% of control, n = 5, not significant), or RBF (99.0% ± 0.4% of control, n = 5, not significant). In clinical practice, the dose ranges for IV tramadol administration in pain control are approximately 1–3 mg/kg (14). According to the article by Lintz et al. (15), the tramadol concentration in human serum reaches approximately 600 ng/mL after IV injection of 100 mg. In rats, the tramadol concentration in serum reaches approximately 4 μg/mL after IV injection of 30 mg/kg (16). Therefore, we studied the effects of 0.5–6 mg/kg of tramadol on MAP, HR, and RBF and also tested 30 mg/kg, which is approximately 10 times larger than the dose used in clinical practice. The control levels of MAP, HR, and RBF were 98.2 ± 3.3 mm Hg, 380.4 ± 10.6 bpm, and 155.3 ± 6.4 mV, respectively. Bolus injection of 2 mg/kg tramadol caused a transient increase in blood pressure, which returned to control levels within 1 min of administration (Fig. 1). Tramadol had little effect on RBF. Tramadol administration at clinically-relevant concentrations of 2 and 4 mg/kg significantly increased MAP (to 109.7% ± 4.6% and 110.5% ± 5.1% of control, respectively) and decreased HR (to 97.8% ± 2% and 92.2% ± 5.7% of control, respectively) (Fig. 2, A and B). In contrast, these same doses had almost no effect on cortical RBF (Fig. 2C). Moreover, we tested a large dose of tramadol on RBF. However, it was not affected by tramadol 30 mg/kg (approximately 10 times the dose used in clinical practice). RBF was altered to 95% ± 4% of control (n = 12).
Several investigators have reported that tramadol inhibits reuptake of neurotransmitter monoamines released from nerve endings and regulates the extraneural NE concentration (5,6). These studies suggest that tramadol might affect hemodynamics by increasing the activity of sympathetic nerves, through modulation of amine reuptake. To investigate whether tramadol injection increases the MAP by modulation of NE reuptake, we examined the effects of a bolus injection of tramadol on serum NE levels. Before tramadol injection, serum levels of NE were 149 ± 39.2 pg/mL (n = 6). A bolus injection of tramadol (2 mg/kg) increased the serum NE level to 263 ± 72.3 pg/mL (P < 0.05 versus before tramadol injection;n = 6). We also studied the serum NE concentration when the administration of 0.5 μg/kg NE reduced RBF to 80% of the control in anesthetized rats. The administration of 0.5 μg/kg NE to anesthetized rats reduced RBF to 80% of the control at a serum NE concentration of 5676 ± 1077 pg/mL (n = 5).
Continuous infusion of tramadol has recently been used for postoperative analgesia (17–19). Therefore, we also examined the effects of continuous tramadol infusion (0.5–4 mg · kg−1 · h−1;n = 6) on MAP, HR, and RBF (Fig. 3). After surgery and the 60-min equilibration period, we increased the doses by 0.5 or 1 mg · kg−1 · h−1 every 40 min (0.5–4 mg · kg−1 · h−1). Tramadol (0.5–4 mg · kg−1 · h−1;n = 6) was continuously administered every 40 min, and MAP, HR, and RBF were measured. The control levels of MAP, HR, and RBF were 100.2 ± 5.9 mm Hg, 344.0 ± 38.5 bpm, and 160.3 ± 9.3 mV, respectively. In contrast to bolus injection of tramadol, continuous infusion had little effect on MAP, HR, or RBF at any dose.
The injection of antibody directed against the Thy 1.1 antigen on the mesangial cell surface in rats induces mesangioproliferative glomerulonephritis (20), with a decrease in RBF and glomerular filtration rate (21). Therefore, this model has been used as an animal model of renal insufficiency caused by mesangioproliferative glomerulonephritis (20). To investigate whether tramadol restores RBF in rats with renal insufficiency, we next examined the effects of tramadol (1–6 mg/kg;n = 6) on rats with renal insufficiency induced by the administration of anti-Thy 1.1 antibody. The following findings were used to confirm that such treatment with anti-Thy 1.1 antibody had induced nephritis: increased serum BUN (17.4 ± 0.7 mg/dL in rats treated with anti-Thy 1.1 [n = 10] vs 13.9 ± 1.4 mg/dL in control rats [n = 4];P < 0.001); increased Cr (0.17 ± 0.04 mg/dL in rats treated with anti-Thy 1.1 [n = 10] vs 0.15 ± 0.02 mg/dL in normal rats [n = 4];P < 0.05); and morphological changes of the glomeruli. In the kidney of the rats with anti-Thy 1.1-induced nephritis, mesangium cells were proliferated in the glomeruli (Fig. 4). The control levels of MAP, HR, and RBF were 104.4 ± 2.9 mm Hg, 358.1 ± 8.1 bpm, and 144.3 ± 11.4 mV, respectively. In nephritic rats, tramadol administration at 2 and 4 mg/kg increased MAP to 108.4% ± 0.7% and 110.6% ± 1.9% of control and decreased HR to 95.1% ± 1.5% and 95% ± 0.2% of control, respectively (Fig. 5, A and B). In contrast, tramadol did not significantly alter RBF in the rats with renal insufficiency (Fig. 5C).
This study found that tramadol failed to alter cortical RBF at clinical doses, even though it increased MAP (possibly because of increased serum NE levels). Tramadol did not change RBF in normal rats, even at 30 mg/kg (a dose much larger than that used clinically). By use of laser Doppler flowmetry, RBF on the surface of the kidney (reflecting RBF in the renal cortex) was directly and continuously measured. The renal cortex contains most of the glomeruli, receives most of the blood flow to the kidney, and is responsible for 90% of total renal function (22). Our results suggest that RBF is maintained during the administration of clinical doses of tramadol. Tramadol also did not affect RBF in rats with experimentally induced renal insufficiency (affected by the administration of anti-Thy 1.1 antibodies). These findings are the first to report the lack of effect of tramadol on RBF.
RBF is regulated by cardiac output and renal vascular resistance (23). Renal vasoconstriction by adrenergic nerve stimulation induces renal hypoperfusion because of reduced renal blood volume (24,25), and increased serum NE also decreases RBF by increasing renal vascular resistance. A significant positive correlation has been reported between sympathetic nerve activity and the increased NE serum levels (26). We showed that a bolus injection of tramadol increased MAP and serum NE, suggesting that tramadol activates the sympathetic nervous system. Müller and Wilsmann (27) reported that tramadol, at clinically relevant concentrations, slightly increases arterial blood pressure without influencing cardiac output in anesthetized rabbits, suggesting that delayed inactivation of endogenously-released NE by inhibition of neuronal NE uptake by tramadol might be responsible for the slight hypertensive and positive chronotropic effects in vivo. The increase of MAP and serum NE by bolus injection of tramadol was caused by inhibition of NE uptake, and our interpretation was supported by the report by Müller and Wilsmann.
This raises the question of why tramadol did not change RBF despite its increased serum NE levels and subsequently increased MAP. Tramadol increased serum NE, but the maximal serum NE concentration that it induced was 360 pg/mL—a concentration considered too small to reduce RBF (although it did transiently increase MAP). Thus, tramadol had little, if any, effect on RBF, even though it increased serum NE. In contrast to the bolus injection of tramadol, continuous injection of tramadol did not have any effects on RBF, HR, or MAP. The question then arises: why did continuously infused increasing doses of tramadol have no effect on MAP, HR, or RBF? Increasing the serum levels of tramadol by continuous infusion would be slower than bolus injection, and the effects on sympathetic nervous activity would be few. Therefore, the continuous infusion of tramadol did not affect MAP, HR, or RBF. Alternatively, tramadol may have direct effects in the kidney and may maintain RBF by unidentified mechanisms. Although the intracellular mechanisms of tramadol are still unknown, another possibility is that it elicits opposing effects to those induced intracellularly by NE.
Although they often cause renal dysfunction, possibly via inhibition of prostaglandin synthesis in the kidney, common NSAID analgesics are widely used. Patients with underlying renal disease are at particular risk of NSAID-induced renal failure (3,4). Our results showed that tramadol did not change renal hemodynamics in either normal rats or in those with renal insufficiency. Moreover, continuous infusion of tramadol did not have an effect on RBF and did not affect blood pressure or HR, suggesting that continuous infusion of tramadol maintains renal hemodynamics. In this study, we investigated the effects of tramadol on cortical RBF, MAP, and HR. Nevertheless, these findings suggest that tramadol, and especially a continuous infusion of tramadol, would be a safe analgesic for patients with intrinsic renal disease.
In conclusion, we showed that tramadol did not alter RBF, even though it increased MAP and decreased HR in both normal rats and in those with renal insufficiency. Although further investigations are needed to assess the effects of tramadol on global renal function, these findings tentatively suggest that tramadol might be a safe analgesic for maintaining RBF.
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