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Tramadol is an analgesic that is used worldwide for pain, but its mechanisms of action have not been fully elucidated. The majority of studies to date have focused on activation of the μ-opioid receptor (μOR) and inhibition of monoamine reuptake as mechanisms of tramadol. Although it has been speculated that tramadol acts primarily through activation of the μOR, no evidence has revealed whether tramadol directly activates the μOR. During the past decade, major advances have been made in our understanding of the physiology and pharmacology of ion channels and G protein-coupled receptor (GPCR) signaling. Several studies have shown that GPCRs and ion channels are targets for tramadol. In particular, tramadol has been shown to affect GPCRs. Here, the effects of tramadol on GPCRs, monoamine transporters, and ion channels are presented with a discussion of recent research on the mechanisms of tramadol.

Sevoflurane is widely used for anesthesia, and is commonly used together with opioids in clinical practice. However, the effects of sevoflurane on µ-opioid receptor (µOR) functions is still unclear. In this study, the effects of sevoflurane on µOR functions were analyzed by using Xenopus oocytes expressing a µOR fused to chimeric Gα protein Gqi5 (µOR-Gqi5). Sevoflurane by itself did not elicit any currents in oocytes expressing µOR-Gqi5, whereas sevoflurane inhibited the [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO)-induced Cl– currents at clinically used concentrations. Sevoflurane did not affect the Cl– currents induced by AlF4–, which directly led to activation of G proteins. The inhibitory effects of sevoflurane on the DAMGO-induced currents were not observed in oocytes pretreated with the protein kinase C (PKC) inhibitor GF109203X. These findings suggest that sevoflurane would inhibit µOR function. Further, the mechanism of inhibition by sevoflurane would be mediated by PKC.

Tramadol has been widely used as analgesic. O-Desmethyl tramadol (ODT) is one of the main metabolites of tramadol, having much greater analgesic potency than tramadol itself. Substance P receptors (SPR) are well known to modulate nociceptive transmission within the spinal cord. In this study, we investigated the effects of ODT on SPR expressed in Xenopus oocytes by examining SP-induced Ca2+-activated Cl− currents. ODT inhibited the SPR-induced Cl− currents at pharmacologically relevant concentrations. The protein kinase C (PKC) inhibitor bisindolylmaleimide I did not abolish the inhibitory effects of ODT on SP-induced Ca2+-activated Cl− currents. The results suggest that the tramadol metabolite ODT inhibits the SPR functions, which may be independent of activation of PKC-mediated pathways. Keywords:: O-desmethyl tramadol (ODT), tramadol, substance P

Purpose: Tramadol is widely used clinically as an analgesic, yet the mechanism by which it produces antinociception remains unclear. O-Desmethyl tramadol, the main metabolite of tramadol, is a more potent analgesic than tramadol. We reported previously that tramadol inhibits the 5-hydroxytryptamine (5-HT) type 2C receptor (5-HT2CR), a G-protein-coupled receptor that is expressed widely within brain and that mediates several effects of 5-HT, including nociception, feeding, and locomotion. The effects of O-desmethyl tramadol on 5-HT2CR have not been studied. In this study, we investigated the effect of O-desmethyl tramadol on 5-HT2CR expressed in Xenopus oocytes. Methods: We examined the effect of O-desmethyl tramadol on 5-HT2CR using the Xenopus oocyte expression system. Furthermore, we investigated the effects of O-desmethyl tramadol on the binding of [3H]5-HT by 5-HT2CR. Results: O-Desmethyl tramadol, at pharmacologically relevant concentrations, inhibited 5-HT-evoked Ca2+-activated Cl– currents in oocytes that expressed 5-HT2CR. The inhibitory effect of O-desmethyl tramadol on 5-HT2CR was overcome at higher concentrations of 5-HT. Bisindolylmaleimide I (GF109203X), a protein kinase C inhibitor, increased 5-HT-evoked currents but had little effect on the inhibition of 5-HT-evoked currents by O-desmethyl tramadol. O-Desmethyl tramadol inhibited the specific binding of [3H]5-HT by 5-HT2CR expressed in oocytes. O-Desmethyl tramadol altered the apparent dissociation constant for binding of [3H]5-HT by 5-HT2CR without changing maximum binding, which indicated competitive inhibition. Conclusion: These results suggest that O-desmethyl tramadol inhibits 5-HT2CR, which provides further insight into the pharmacological properties of tramadol and O-desmethyl tramadol.

O-desmethyl tramadol is one of the main metabolites of tramadol. It has been widely used clinically and has analgesic activity. Muscarinic receptors are involved in neuronal functions in the brain and autonomic nervous system, and much attention has been paid to these receptors as targets for analgesic drugs in the central nervous system. We have reported that tramadol inhibits the function of type-1 muscarinic (M(1)) receptors and type-3 muscarinic (M(3)) receptors, suggesting that muscarinic receptors are sites of action of tramadol. However, the effects of O-desmethyl tramadol on muscarinic receptor functions have not been studied in detail. In this study, we investigated the effects of O-desmethyl tramadol on M(1) and M(3) receptors, using the Xenopus oocyte expression system. O-desmethyl tramadol (0.1-100 microM) inhibited acetylcholine (ACh)-induced currents in oocytes expressing the M(1) receptors (half-maximal inhibitory concentration [IC(50)] = 2 +/- 0.6 microM), whereas it did not suppress ACh-induced currents in oocytes expressing the M(3) receptor. Although GF109203X, a protein kinase C inhibitor, increased the ACh-induced current, it had little effect on the inhibition of ACh-induced currents by O-desmethyl tramadol in oocytes expressing M(1) receptors. The inhibitory effect of O-desmethyl tramadol on M(1) receptor was overcome when the concentration of ACh was increased (K(D) with O-desmethyl tramadol = 0.3 microM). O-desmethyl tramadol inhibited the specific binding of [(3)H]quinuclidinyl benzilate ([(3)H]QNB) to the oocytes expressed M(1) receptors (IC(50) = 10.1 +/- 0.1 microM), whereas it did not suppress the specific binding of [(3)H]QNB to the oocytes expressed M(3) receptors. Based on these results, O-desmethyl tramadol inhibits functions of M(1) receptors but has little effect on those of M(3) receptors. This study demonstrates the molecular action of O-desmethyl tramadol on the receptors and may help to explain its neural function.

Tramadol, [(1RS, 2RS)-2-dimethylamino) methyl-1-(3-methoxyphenyl)-cyclohexanol hydrochloride], is an analgesic in clinical use. It has been reported that tramadol inhibits muscarinic type 3 receptor function, which primarily mediates smooth muscle contraction and glandular secretion. We investigated the effects of tramadol on the pH of gastric juices during anesthesia to determine whether tramadol inhibits secretion from the gastric glands.ASA physical status I or II adult patients (n = 30) presenting for major elective orthopedic surgery of the upper extremities or mastectomy were enrolled. Patients were randomly assigned to receive treatment with tramadol (n = 10), famotidine (n = 10), or saline (n = 10). General anesthesia was then induced using propofol, vecuronium bromide, and fentanyl. After inducing anesthesia, the gastric pH was measured using pH test paper and, then, 100 mg tramadol, 20 mg famotidine, or saline were injected into the deltoid muscle. Three hours after starting the operation, gastric juice was again aspirated and its gastric pH measured.There were no differences in the pH before anesthesia between the three groups. By contrast, gastric pH was increased in the tramadol group by the same amount as it was in the famotidine group three hours after administering the drugs. Gastric pH of the saline, famotidine, and tramadol groups was 2.6 +/- 2.5, 6.3 +/- 2.0, and 6.4 +/- 0.8, respectively.These results suggest that tramadol inhibits the secretion of gastric acid.

Metabotropic G protein-coupled receptors have recently been recognized as targets for anesthetics and analgesics. In particular, Gq-coupled receptors such as muscarinic M1 receptors (M1R) and 5-hydroxytryptamine (5-HT) type 2A receptors have been reported to be targets for anesthetics. Much less is known, however, about the effects of anesthetics on Gi-coupled receptors. Here we report a method to analyze functions of Gi-coupled receptors in Xenopus oocytes expressing a chimeric Gα protein. A chimeric Gαq protein Gαqi5, which contains carboxy-terminus five amino acids of Gαi, enables Gi-coupled receptors to couple to Gq-coupled receptor-mediated downstream pathways such as activation of phospholipase C. We determined acetylcholine (ACh)-induced Ca2+-activated Cl– currents in Xenopus oocytes coexpressing Gi-coupled muscarinic M2 receptors (M2R) with the chimeric Gαqi5. Although ACh did not induce any currents in oocytes expressing M2R alone, it caused robust Cl– currents in oocytes coexpressing M2R with Gαqi5. The EC50 of the ACh-induced Cl– current mediated through Gαqi5 was 0.2 µmol/l, which was 2.2 times higher than that of the ACh-induced G protein-activated inwardly rectifying K+ currents activated by Gβγ subunits liberated from endogenously expressed Gαi in Xenopus oocytes. Other Gi-coupled somatostatin type 2, 5-HT1A and δ-opioid receptors, when coexpressed with Gαqi5 in oocytes, also caused robust Ca2+-activated Cl– currents. In oocytes coexpressing M2R and Gαqi5, a volatile anesthetic halothane inhibited M2R-induced Cl– currents in a concentration-dependent manner with the IC50 of 1.1 mmol/l, suggesting that halothane inhibits M2R-induced cellular responses at clinically relevant concentrations. Treatment with the protein kinase C inhibitor GF109203X produced a 3.5-fold enhancement of the initial Cl– currents induced by 1 µmol/l ACh in oocytes expressing M2R and Gqi5. The rate of halothane-induced inhibition of Cl– currents elicited by ACh, however, was not changed in such oocytes pretreated with GF109203X. These findings suggest that halothane inhibits the M2R-induced signaling by acting at sites other than PKC activity. Collectively these findings suggest that the use of oocyte expressing Gαqi5 would be helpful to examine the effects of anesthetics or analgesics on the function of Gi-coupled receptors in the Xenopus oocyte expression system.

UNLABELLED Alphaxalone is a neurosteroid anesthetic, but its mechanisms of action are not completely understood. Muscarinic receptors are involved in a variety of neuronal functions in the brain and autonomic nervous system, and much attention has been paid to them as targets of anesthetics. In this study, we investigated the effects of alphaxalone on M(1) and M(3) muscarinic receptors using the Xenopus oocyte expression system. Alphaxalone inhibited acetylcholine-induced currents in oocytes expressing M(1) receptors at clinically relevant concentrations. Alphaxalone also suppressed acetylcholine-induced currents in oocytes expressing M(3) receptors. The half-maximal inhibitory concentration values for the inhibition of M(1)- and M(3)-mediated currents were 1.8 +/- 0.6 micro M and 5.3 +/- 1.0 micro M, respectively. GF109203X, a selective protein kinase C inhibitor, had little effect on the inhibition of acetylcholine-induced currents by alphaxalone in oocytes expressing these receptors. Alphaxalone inhibited the specific binding of [(3)H]quinuclidinyl benzilate to oocytes expressing M(1) or M(3) receptors. These findings suggest that alphaxalone at clinically relevant concentrations inhibits the function of M(1) and M(3) receptors through a protein kinase C-independent mechanism by interfering with the [(3)H]quinuclidinyl benzilate binding sites on the receptors. IMPLICATIONS Alphaxalone, a neurosteroid anesthetic, inhibited the function of muscarinic M(1) and M(3) receptors and the specific binding of [(3)H]quinuclidinyl benzilate ([(3)H]QNB) to oocytes expressing these receptors. These findings suggest that alphaxalone inhibits these receptors by interfering with the QNB binding sites.

Kisspeptin is the natural ligand of the G protein-coupled receptor -54 and plays a major role in gonadotropin-releasing hormone secretion in the hypothalamus. Kisspeptin-10 is an endogenous derivative of kisspeptin and has 10 -amino acids. Previous studies have demonstrated that central administration of kisspeptin-10 stimulates the secretion of arginine vasopressin (AVP) in male rats. We examined the effects of kisspeptin-10 on- excitatory synaptic inputs to magnocellular neurosecretory cells (MNCs) including AVP neurons in the supraoptic nucleus (SON) by obtaining in vitro whole-cell patch-clamp recordings from slice preparations of the rat brain. The application of kisspeptin-10 (100 nM–1 μM) significantly increased the frequency of miniature excitatory postsynaptic currents (mEPSCs) in a dose-related manner without affecting the amplitude. The kisspeptin-10-induced potentiation of the mEPSCs was significantly attenuated by previous exposure to the kisspeptin receptor antagonist kisspeptin-234 (100 nM) and to the protein kinase C inhibitor bisindolylmaleimide I (20 nM). These results suggest that kisspeptin-10 participates in the regulation of synaptic inputs to the MNCs in the SON by interacting with the kisspeptin receptor.

UNLABELLED Although transient sialadenopathy of the submandibular gland associated with insertion of the laryngeal mask airway (LMA) has been described, the influence of the LMA on the submandibular gland is unknown. We measured the width and length of the submandibular glands by using ultrasonography in patients in whom the LMA was used. An increased intracuff pressure of the LMA, up to 150 cm H2O, was used in a prospective study of adult patients scheduled for elective surgery. The width of the gland increased with an increasing intracuff pressure from 50 to 100 cm H2O (P < 0.01) and 100 to 150 cm H2O (P < 0.01) but did not change from 0 to 50 cm H2O. There was no change in the length of the gland. We conclude that the submandibular gland was deformed by the insertion of the LMA. IMPLICATIONS The findings in our study show that the submandibular triangle can be easily compressed by the insertion of the laryngeal mask airway (LMA). When inserting the LMA, it is important to consider that the LMA cuff may alter these tissues, which are situated between the lingual root and the submandibular triangle.

Adrenomedullin (AM), a hypotensive peptide originally isolated from human pheochromocytoma, has been reported to regulate renal functions. In patients with glomerulonephritis, the serum levels of AM are elevated as well as hypertensive agents norepinephrine (NE) and angiotensin II (AII). The effects of AM on the NE- or AII-induced pressor effects and renal blood flow responses, however, are not well clarified. We examined the effects of AM on blood pressure and renal blood flow induced by NE or AII in anesthetized rats. Arterial blood pressure and renal blood flow were measured using a calibrated pressure transducer and a laser Doppler flowmeter, respectively. Drugs were injected into the tail vein with a syringe. Intravenous administration of AM (1-3 nmol/kg) decreased the arterial blood pressure in anesthetized rats in a dose-dependent manner, whereas it did not affect the renal blood flow. NE or AII administration in anesthetized rats caused both increases in blood pressure and decreases in renal blood flow. Simultaneous administration of AM with NE or All prevented the increasing effects of blood pressure and inhibited the decreases in renal blood flow caused by NE or AII. These findings suggest that AM may have a protective role against the pressor effects and decrease in renal blood flow caused by NE or AII.

Volatile anesthetics attenuate medium-frequency (250 to 500 Hz) pulse train transcranial electrical stimulation (TES) motor-evoked potentials (MEPs) better than propofol. High-frequency (1000 Hz) TES may restore hand MEP amplitude under volatile anesthesia, but its effect on leg MEPs critical for spine surgery monitoring is unknown.The effects of sevoflurane and propofol and modulation of the stimulation frequencies on MEPs elicited by TES in the anterior tibial, abductor hallucis, and abductor pollicic brevis muscles were investigated in 31 patients undergoing spine surgery. MEPs elicited by transcranial magnetic stimulation were also obtained before the surgeries and compared with the TES MEPs.Sevoflurane attenuated the MEP amplitudes significantly. The MEP amplitudes increased with the TES frequency in the case of the arms, but not the legs, under sevoflurane anesthesia. The MEPs recorded under propofol anesthesia did not differ from those elicited by transcranial magnetic stimulation before the surgery (control).Sevoflurane is inadvisable for MEP monitoring in the legs during spine surgery as modulation of the TES frequency did not eliminate the suppressive effect of sevoflurane on the MEPs in the legs. Clinicians should be forewarned of the greater risk of unmonitorable MEPs, especially in the legs, under sevoflurane anesthesia.

Sevoflurane is widely used as a volatile anesthetic in clinical practice. However, its mechanism is still unclear. Recently, it has been reported that voltage-gated sodium channels have important roles in anesthetic mechanisms. Much attention has been paid to the effects of sevoflurane on voltage-dependent sodium channels. To elucidate this, we examined the effects of sevoflurane on Na(v) 1.8, Na(v) 1.4, and Na(v) 1.7 expressed in Xenopus oocytes. The effects of sevoflurane on Na(v) 1.8, Na(v) 1.4, and Na(v) 1.7 sodium channels were studied by an electrophysiology method using whole-cell, two-electrode voltage-clamp techniques in Xenopus oocytes. Sevoflurane at 1.0 mM inhibited the voltage-gated sodium channels Na(v)1.8, Na(v)1.4, and Na(v)1.7, but sevoflurane (0.5 mM) had little effect. This inhibitory effect of 1 mM sevoflurane was completely abolished by pretreatment with protein kinase C (PKC) inhibitor, bisindolylmaleimide I. Sevoflurane appears to have inhibitory effects on Na(v)1.8, Na(v)1.4, and Na(v) 1.7 by PKC pathways. However, these sodium channels might not be related to the clinical anesthetic effects of sevoflurane.

Sevoflurane is widely used for anesthesia, and is commonly used together with opioids in clinical practice. However, the effects of sevoflurane on μ-opioid receptor (μOR) functions is still unclear. In this study, the effects of sevoflurane on μOR functions were analyzed by using Xenopus oocytes expressing a μOR fused to chimeric Gα protein G(qi5) (μOR-G(qi5)). Sevoflurane by itself did not elicit any currents in oocytes expressing μOR-G(qi5), whereas sevoflurane inhibited the [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO)-induced Cl(-) currents at clinically used concentrations. Sevoflurane did not affect the Cl(-) currents induced by AlF(4)(-), which directly led to activation of G proteins. The inhibitory effects of sevoflurane on the DAMGO-induced currents were not observed in oocytes pretreated with the protein kinase C (PKC) inhibitor GF109203X. These findings suggest that sevoflurane would inhibit μOR function. Further, the mechanism of inhibition by sevoflurane would be mediated by PKC.

Polysomnography (PSG) has been the gold standard for the diagnosis of sleep apnea syndrome (SAS). However, PSG is not generally available since it is technically demanding, and cost and labour are necessary. Currently, there is growing demand for its diagnosis. Thus, simplified portable equipments have been increasingly utilized. Sleeprecorder SD-101 (Suzuken, Nagoya, Japan) is a pad-shaped and novel device for SAS analysis. A total of 162 sitting-sensor tips are 1.6 inch apart, embeded in the 55 x 22 inch pad, and capable of detecting load with precision of one gram. Sleeprecorder SD-101 placed beneath the chest can recognize respiratory pattern and record thoracic movement during sleep. SASLyzer (Suzuken, Nagoya, Japan), a software installed in a compatible PC, analyzes the data and indicates apnea-hypopnea index (AHI). We present a case of SAS in a 40-year-old man (181 cm, 98 kg) with peritonsillitis. We used Sleeprecorder SD-101 since he complained of severe snoring and excessive daytime sleepiness. He had severe SAS with AHI 50.7. Subsequently, conventional PSG also indicated AHI 77. In the present case with severe SAS, these two methods showed equivalent severity. Sleeprecorder SD-101 could be a useful device for screening of SAS patients.

Alkaptonuric ochronosis, caused by a deficiency of homogentisate 1,2-dioxygenase, is a rare, autosomal recessive, metabolic disorder. Accumulation of homogentisate acid (HGA) at the connective tissue destructs the spine and large joints, and cardiac valvular disease is prominent. In this report, we describe a case of alkaptonuric ochronosis for anesthetic management. A 75-year-old female patient with the disease was scheduled for a total-hip arthroplasty. We avoided applying general anesthesia for her valvular regurgitations. Spinal anesthesia was achieved successfully, and resulted in a hypesthesia level at T12. Although a epidural catheter was indwelled with no leak of cerebrospinal fluid, an accidental dural puncture appeared later during the surgery, suggesting a subdural catheterization. She had an uneventful perioperative course without any symptoms. In the patient of alkaptonuric ochronosis, the dura and arachnoid membrane could be damaged made vulnerable by HGA. In addition, since the clinical findings resemble ankylosing spondylitis, degenerative changes such as a narrowing of the disk space and spine fusion would make the regional technique unsuccessful. In term of anesthesia, alkaptonuric ochronosis requires ingenuity since there are a number of factors associated with prevention of untoward complications. Each case is to be evaluated individually and managed carefully.

In the failing heart, numerous changes occur in cardiac adrenergic receptors (ARs) and intracellular signal transduction pathways. The most striking of these alterations appears at beta1 ARs, and the desensitization is the most prominent. Since malfunctions of beta1 ARs prevent intracellular signal transduction, the desensitization plays an important role in the onset and progression of the heart failure. Currently, several lines of evidence show the efficacy of inotropic agents, such as adenylate cyclase activator, that depend not on the ARs. Thus, it is essential to understand the pathway for the etiologic/pathologic evaluation for appropriate usage of these drugs for an adequate period. A novel water-soluble forskolin derivative, colforsin daropate hydrochloride (CDH) is a positive inotropic agent for treatment of the heart failure, especially in the severe stage with the beta1 AR desensitization. CDH potentiates cAMP activity via its direct action on adenylate cyclase, resulting in cardiotonic action. On the other hand, CDH relaxes vascular smooth muscle, while it antagonizes antidiuretic effects of angiotensin II and noradrenaline, involved in renal protection. In addition, CDH attenuates the mesangial cell proliferation and the inflammatory reaction, related with antiproliferative property of adrenomedullin and ketamine. To gain insights into the CDH action, we should take into account that intracellular signal transduction pathways in myocardium, smooth muscle and mesangial cell are controlled in a distinct manner.

Alcohols, inhaled anesthetics, and some injectable anesthetics inhibit the function of N-methyl-d-aspartate (NMDA) receptors, but the mechanisms responsible for this inhibition are not fully understood. Recently, it was shown that ethanol inhibition of NMDA receptors was reduced by mutation of residues in the transmembrane (TM) segment 3 of the NR1 subunit (F639A) or in TM4 of the NR2A subunit (A825W), suggesting putative ethanol binding sites. We hypothesized that the actions of other anesthetics might also require these amino acids and evaluated the effects of anesthetics on the NMDA receptors expressed in Xenopus oocytes with two-electrode voltage-clamp recording. Effects of hexanol, octanol, isoflurane, halothane, chloroform, cyclopropane, 1-chloro-1,2,2-trifluorocyclobutane, and xenon were reduced or eliminated in the mutant NMDA receptors, whereas the inhibitory effects of nitrous oxide, ketamine, and benzene were not affected by these mutations. Rapid applications of glutamate and glycine by a T-tube device provided activation time constants, which suggested different properties of ketamine and isoflurane inhibition. Thus, amino acids in TM3 and TM4 are important for the actions of many anesthetics, but nitrous oxide, benzene, and ketamine seem to have distinct mechanisms for inhibition of the NMDA receptors.

Tramadol is widely used clinically as an analgesic, yet the mechanism by which it produces antinociception remains unclear. O-Desmethyl tramadol, the main metabolite of tramadol, is a more potent analgesic than tramadol. We reported previously that tramadol inhibits the 5-hydroxytryptamine (5-HT) type 2C receptor (5-HT(2C)R), a G-protein-coupled receptor that is expressed widely within brain and that mediates several effects of 5-HT, including nociception, feeding, and locomotion. The effects of O-desmethyl tramadol on 5-HT(2C)R have not been studied. In this study, we investigated the effect of O-desmethyl tramadol on 5-HT(2C)R expressed in Xenopus oocytes.We examined the effect of O-desmethyl tramadol on 5-HT(2C)R using the Xenopus oocyte expression system. Furthermore, we investigated the effects of O-desmethyl tramadol on the binding of [(3)H]5-HT by 5-HT(2C)R.O-Desmethyl tramadol, at pharmacologically relevant concentrations, inhibited 5-HT-evoked Ca(2+)-activated Cl(-) currents in oocytes that expressed 5-HT(2C)R. The inhibitory effect of O-desmethyl tramadol on 5-HT(2C)R was overcome at higher concentrations of 5-HT. Bisindolylmaleimide I (GF109203X), a protein kinase C inhibitor, increased 5-HT-evoked currents but had little effect on the inhibition of 5-HT-evoked currents by O-desmethyl tramadol. O-Desmethyl tramadol inhibited the specific binding of [(3)H]5-HT by 5-HT(2C)R expressed in oocytes. O-Desmethyl tramadol altered the apparent dissociation constant for binding of [(3)H]5-HT by 5-HT(2C)R without changing maximum binding, which indicated competitive inhibition.These results suggest that O-desmethyl tramadol inhibits 5-HT(2C)R, which provides further insight into the pharmacological properties of tramadol and O-desmethyl tramadol.

Complications related to anesthesia remain a problem. We studied the incidence of complications during anesthesia in 2688 patients who had undergone anesthesia in the University of Occupational and Environmental Health Hospital.We checked the anesthesia records retrospectively and analyzed the collected data for the incidence of complications during anesthesia.The total incidence of complications during anesthesia was 8.7%:5.5% related to circulation and 1.9% to respiration.Complications related to anesthesia should be prevented as much as possible through anesthesiologists' efforts in protocol development and skilled assistance.

Complications related to anesthesia remain a problem. We studied the incidence of complications during anesthesia in 2758 patients who had undergone anesthesia in the University of Occupational and Environmental Health Hospital.We checked the anesthesia records retrospectively and analyzed the collected data for the incidence of complications during anesthesia.The total incidence of complications during anesthesia was 12.2%. The incidences of complication are estimated to be 13.4% in inhalation anesthesia, 11.9% in inhalation anesthesia plus epidural, spinal or conduction block, 8.9% in CSEA, zero % in epidural anesthesia and 7.5% in spinal anesthesia.The incidence of complications in inhalation anesthesia was almost as same as that in inhalation anesthesia plus epidural, spinal or conduction block. More study should be necessary to prevent complications related to anesthesia.

A 9-year-old boy was scheduled for excision of tracheal granuloma which had developed at the tip of a tracheostomy tube. Instead of a tracheostomy tube, a 4 mm ID tracheal tube was inserted via the tracheostomy beyond the tracheal constriction because of rapid development of respiratory failure. General anesthesia was induced and maintained with sevoflurane and oxygen via the tube, and a size 2.5 laryngeal mask airway (LMA) was inserted without muscle relaxant. Spontaneous respiration remained. Under monitoring by fiberoptic tracheoscopy via the LMA, the tracheal tube was extubated carefully. An 8 Fr. suction tube was indwelled via the tracheostomy beyond the stenosis for oxygen supply. After sealing the tracheostomy, he could breath spontaneously through the LMA. During the excision of tracheal granuloma by holmium:YAG laser, fiberoptic observation was continued via the LMA, and the procedure was performed without any complication. We conclude that the tracheal stenosis can be managed using the LMA, continuous fiberoptic monitoring and additional option of keeping spontaneous ventilation.

A 71-year-old man was scheduled for an extirpation of chronic expanding hematoma (CEH) of his right thorax. He had a history of right thoracoplasty for tuberculosis 37 years previously. He complained of dyspnea that had deteriorated over three months. His inflammatory responses including general fatigue and fever due to chronic empyema remained to be resolved. The chest computed tomography revealed that the CEH remarkably compressed the trachea and the heart resulting in the cause of left mediastinal deviation. General anesthesia was induced with fentanyl and propofol, and maintained with sevoflurane. During general anesthesia, mean central venous pressure (CVP) via the right femoral vein and arterial blood pressure (ABP) via the left radial artery were monitored. Bilateral peripheral vein catheters with 16 G could effectively provide huge amount of transfusion. Although his blood loss was 10,000 ml because of superior vena caval rupture and oozing from pleura, prompt and adequate management of hemodynamics could be maintained using CVP and ABP monitoring. The CEH is known as a specific type of chronic empyema and its extraction would require ingenuity since there are number of factors associated with diagnosis, indication and prevention. Each case is to be evaluated individually and managed carefully.

Nosocomial pneumonia remains a common complication in patients undergoing endotracheal intubation. This study examined the transport of bacteria into the trachea during endotracheal intubation, and evaluated the effects of gargling with povidone-iodine on bacterial contamination of the tip of the intubation tube.In the gargling group, patients gargled with 25 mL of povidone-iodine (2.5 mg.mL(-1)). In the control group, patients gargled with 25 mL of tap water. Before tracheal intubation, microorganisms were obtained from the posterior wall of the patient's pharynx using sterile cotton swabs. After anesthesia, all patients were extubated and bacteria contaminating the tip of the tracheal tube were sampled and cultured.Before orotracheal intubation, all 19 patients who gargled with tap water (control group) had bacterial colonization on the posterior walls of the pharynx. This group included five patients who had methicillin-resistant staphylococcus aureus (MRSA) in their nasal cavity preoperatively and MRSA was also detected in the pharynx of four patients. Bacterial colonization was observed in all 19 patients who gargled with povidone-iodine (gargling group) and four patients carried MRSA in their nasal cavity, although no MRSA was detected in the pharynx. In the control group, all the patients had bacterial colonization at the tip of the tube after extubation. Additionally, MRSA was detected in two of the four patients. In the gargling group, povidone-iodine eradicated general bacteria and MRSA colonies in the pharynx before intubation and at the tip of the tube after extubation.Gargling with povidone-iodine before oral intubation reduces the transport of bacteria into the trachea.

Calciphylaxis is a small-vessel disease associated with renal failure. Here, we report the management of a 43-yr-old man with calciphylaxis who received left lower leg amputation with prostaglandin E(1) (PGE(1)) under monitoring by laser Doppler blood flowmetry in the left second and third fingers. Anesthesia was induced with midazolam, fentanyl, and vecuronium and was maintained with oxygen, nitrous oxide, and sevoflurane. The peripheral blood flow varied and decreased gradually; therefore, we added PGE(1) 20 ng. kg(-1). min(-1), which increased blood flow of the tissues. Three weeks after the operation, we again anesthetized the patient. We maintained the blood flow with PGE(1) throughout anesthesia. Monitoring by laser Doppler blood flowmetry and PGE(1) 20 ng. kg(-1). min(-1) could be useful for patients with impaired peripheral circulation, as in calciphylaxis.

UNLABELLED Although tramadol is widely available as an analgesic, its mechanism of antinociception remains unresolved. Serotonin (5-hydroxytryptamine, 5-HT) is a monoaminergic neurotransmitter that modulates numerous sensory, motor, and behavioral processes. The 5-HT type 2C receptor (5-HT(2C)R) is one of the major 5-HT receptor subtypes and is implicated in many important effects of 5-HT, including pain, feeding, and locomotion. In this study, we used a whole-cell voltage clamp to examine the effects of tramadol on 5-HT-induced Ca(2+)-activated Cl(-) currents mediated by 5-HT(2C)R expressed in Xenopus oocytes. Tramadol inhibited 5-HT-induced Cl(-) currents at pharmacologically relevant concentrations. The protein kinase C (PKC) inhibitor, bisindolylmaleimide I (GF109203x), did not abolish the inhibitory effects of tramadol on the 5-HT(2C)R-mediated events. We also studied the effects of tramadol on [(3)H]5-HT binding to 5-HT(2C)R expressed in Xenopus oocytes, and found that it inhibited the specific binding of [(3)H]5-HT to 5-HT(2C)R. Scatchard analysis of [(3)H]5-HT binding revealed that tramadol altered the apparent dissociation constant for binding without changing maximal binding, indicating competitive inhibition. The results suggest that tramadol inhibits 5-HT(2C)R function, and the mechanism of this inhibitory effect seems to involve competitive displacement of the 5-HT binding to the 5-HT(2C)R, rather than via activation of the PKC pathway. IMPLICATIONS We examined the effects of tramadol on 5-hydroxytryptamine type 2C receptor (5-HT(2C)R) expressed in Xenopus oocytes. Tramadol inhibited 5-HT(2C)R function and the specific binding of [(3)H]5-HT to 5-HT(2C)R in a competitive manner. From these data, the mechanism of the inhibitory effect on 5-HT(2C)R might involve the competitive displacement of 5-HT binding to the 5-HT(2C)R.

The neurosteroids pregnenolone, progesterone, and dehydroepiandrosterone (DHEA) occur naturally in the nervous system. They act on neural tissues, participate in neuronal signaling, and are reported to alter neuronal excitability via nongenomic mechanisms. Muscarinic receptors have important roles in neuronal functions in the brain and autonomic nervous system. In this study, we investigated the effects of pregnenolone, progesterone, and DHEA on M(1) and M(3) muscarinic receptors using the Xenopus oocyte expression system. Pregnenolone and progesterone inhibited the acetylcholine (ACh)-mediated responses of M(1) and M(3) receptors expressed in Xenopus oocytes, whereas DHEA did not. The half-maximal inhibitory concentrations (IC(50)) for pregnenolone inhibition of M(1) receptor- and M(3) receptor-mediated currents were 11.4 and 6.0 microM respectively; the IC(50) values for progesterone inhibition of M(1) receptor- and M(3) receptor-mediated currents were 2.5 and 3.0 microM respectively. The selective protein kinase C (PKC) inhibitor GF109203X had little effect on the pregnenolone or progesterone inhibition of the ACh-induced currents in Xenopus oocytes expressing M(1) or M(3) receptors. The inhibitory effects of pregnenolone and progesterone were overcome at higher concentrations of ACh. Pregnenolone and progesterone inhibited the [(3)H]quinuclidinyl benzilate (QNB) binding to M(1) and M(3) receptor expressed in Xenopus oocytes, and Scatchard plot analysis of [(3)H]QNB binding revealed that pregnenolone and progesterone altered the K(d) value and the B(max), indicating noncompetitive inhibition. In conclusion, pregnenolone and progesterone inhibited M(1) and M(3) receptor functions noncompetitively by the mechanism independent of PKC and by interfering with ACh binding to the receptors.

UNLABELLED Substance P receptors (SPR) modulate nociceptive transmission within the spinal cord. The effects of IV anesthetics on SPR are not clear. In this study, we investigated the effects of IV anesthetics on SPR expressed in Xenopus oocytes. We examined the effects of ketamine, pentobarbital, propofol, and tramadol on SP-induced Ca(2+)-activated Cl(-) currents mediated by SPR expressed in Xenopus oocytes using a whole-cell voltage clamp. Ketamine and pentobarbital inhibited the SPR-induced currents at pharmacologically relevant concentrations, but propofol and tramadol had little effect on the currents. We also studied the effects of ketamine and pentobarbital on [(3)H]-SP to SPR. Ketamine and pentobarbital inhibited the specific binding of [(3)H]-SP to SPR expressed in Xenopus oocytes. Scatchard analysis of [(3)H]-SP binding revealed that ketamine and pentobarbital decreased the apparent dissociation constant for binding and maximal binding, indicating noncompetitive inhibition. The protein kinase C (PKC) inhibitor bisindolylmaleimide I did not abolish the inhibitory effects of ketamine and pentobarbital on SP-induced Ca(2+)-activated Cl(-) currents. The results suggest that ketamine and pentobarbital inhibit SPR function. The mechanism of their inhibition on SPR function could not be through activation of the PKC pathway and may be due to noncompetitive displacing the SP binding. IMPLICATIONS We investigated the effects of IV anesthetics on substance P receptors (SPR) expressed in Xenopus oocytes. Ketamine and pentobarbital inhibit SPR function via noncompetitive displacing SP binding. The findings imply that the inhibition of SPR function by these compounds may play a role in the analgesic effects of these IV anesthetics.

IMPLICATIONS Epirubicin, an anticancer drug, causes cardiotoxicity. We reported a case of sino-atrial block during general anesthesia in a woman with breast cancer who had received epirubicin. Anesthesiologists should be aware of the possible occurrence of sino-atrial block with epirubicin, and planting a pacemaker might be considered even in asymptomatic patients.

A forskolin derivative, colforsin daropate hydrochloride (CDH), acts directly on adenylate cyclase to increase the intracellular cyclic adenosine monophosphate levels which produce a positive inotropic effect and a lower blood pressure. However, little is known about the effects of CDH on the renal function. We used laser Doppler flowmetry to measure the cortical renal blood flow (RBF) in male Wistar rats given a continuous intravenous infusion of CDH and evaluated the effects of CDH on the noradrenaline (NA) and angiotensin II (AngII) induced increases in blood pressure and reductions in RBF. Continuous intravenous administration of CDH at 0.25 µg/kg/min did not affect the mean arterial pressure (MAP), but increased heart rate and RBF. Continuous intravenous administration of CDH at high doses (0.5–0.75 µg/kg/min) decreased the MAP, with little effect on the RBF. The administration of exogenous NA (1.7 µg/kg) increased the MAP and decreased the RBF. However, a bolus injection of NA did not decrease the RBF during continuous intravenous administration of CDH, and CDH did not affect the NA-induced increase in MAP. The administration of exogenous AngII (100 ng/kg) increased MAP and decreased RBF and heart rate, but a bolus injection of AngII did not decrease RBF during continuous intravenous administration of CDH. These results suggest that CDH plays a protective role against the pressor effects and the decrease in RBF induced by NA or AngII.

A forskolin derivative, colforsin daropate hydrochloride (CDH), has been introduced as an inotropic agent that acts directly on adenylate cyclase to increase intracellular cyclic AMP (cAMP) levels and ventricular contractility, resulting in positive inotropic activity. We investigated the effects of CDH on rat mesangial cell (MC) proliferation. CDH (10–7–10–5 mol/l) inhibited [3H]thymidine incorporation into cultured rat MCs in a concentration-dependent manner. CDH (10–7–10–5 mol/l) also decreased cell numbers in a similar manner, and stimulated cAMP accumulation in MCs in a concentration-dependent manner. A protein kinase A inhibitor, H-89, abolished the inhibitory effects of CDH on MC mitogenesis. These findings suggest that CDH would inhibit the proliferation of rat MCs via the cAMP pathway.

The production of proinflammatory cytokines, such as tumor necrosis factor (TNF) a, interleukin (IL)-6, and IL-8, increases in patients with sepsis; marked production causes organ failure and septic shock. We previously reported that ketamine suppressed lipopolysaccharide (LPS)-induced TNF-alpha production in mice. However, there are no reports on the effect of ketamine on cytokine production in human whole blood. Therefore, in this study, we investigated the efficacy of ketamine on LPS-induced TNF-alpha, IL-6, and IL-8 production and recombinant human (rh) TNF-a-induced IL-6 and IL-8 production in human whole blood. After adding different doses of ketamine to whole blood, the blood was stimulated with LPS or rhTNF. After incubation, the plasma TNF-alpha activity and IL-6 and IL-8 concentrations were measured using the L929 cell cytotoxic assay or an enzyme-linked immunoassay. Ketamine significantly suppressed LPS-induced TNF-alpha production at concentrations20 microg/mL. At concentrations100 microg/mL, ketamine also significantly suppressed both LPS-induced and rhTNF-induced IL-6 and IL-8 production. In this study, we demonstrated that ketamine directly inhibits the production of proinflammatory cytokines such as TNF-alpha, IL-6, and IL-8 in human whole blood.We found that ketamine suppressed lipopolysaccharide-induced tumor necrosis factor alpha, interleukin (IL)-6, and IL-8 production and recombinant human tumor necrosis factor-induced IL-6 and IL-8 production in human whole blood. Ketamine directly suppresses proinflammatory cytokine production.

Anesthetics have been reported to suppress NMDA receptor function, however, mechanisms of the inhibition by anesthetics of NMDA receptors are not fully understood. Here, we report a residue in transmembrane 3 (TM3) region of the NR1 subunit of NMDA receptors, which is critical for anesthetic inhibition.

To the Editor: Several reports have indicated that pregnancy predisposes asymptomatic patients with Wolff-ParkinsonWhite (WPW) syndrome to supraventricular tachycardia (SVT).1,2 We report a case of repeated SVT in a 36-yr-old woman with WPW syndrome during anesthesia for Cesarean delivery (C/D). The patient was scheduled for C/D due to cephalopelvic disproportion. WPW syndrome had been diagnosed at age 18, however, she had had no attacks for 18 years and was not taking any medication. Her heart rate (HR) was regular with sinus rhythm before C/D. Mepivacaine (2%; 13 mL) was injected into the epidural space and sensory analgesia reached the T4 level. The baby was born uneventfully and blood losses were 450 mL. At the end of the operation, SVT occurred suddenly, HR increased to 190 beats·min–1 and blood pressure decreased. At first, we tried vagal stimulation (Valsalva maneuver and carotid massage) but the SVT did not stabilize. Next, verapamil (3.7 mg) was administered and the HR stabilized to sinus rhythm. Postoperatively, SVT occurred three other times and we administered verapamil (5 mg) and disopyramide (50 mg) to stabilize the HR. Oxytocin administration, anxiety, pain, etc., have been reported to trigger SVT in parturients with WPW syndrome.3 Because of the timing in our case, it is difficult to say what triggered the SVT exactly. However, anesthesiologists should be aware of the possible recurrence of repeated SVT, even in the asymptomatic patient, with WPW syndrome. 752 CANADIAN JOURNAL OF ANESTHESIA

Contact thermal conductance is much lower in a vacuum than normal pressure conditions. When we cool SR beamline optics, such as mirror components, a water cooled copper plate which is attached to the optics is used. In order to increase the effect on cooling an indium sheet or liquid metal, such as Ga, In-Ga, is inserted between the optics and the plate. We experimentally obtained contact thermal conductance in a vacuum, which was essential to computing the thermal distribution of optics. And we simulated our cooling system using a beamline mirror component.

To the Editor: Ebstein’s malformation is rare congenital heart disease with the downward displacement of the tricuspid valve into the right ventricle. The hazards occurs tachydysrhythmias and hypoxemia owing to the rightto-left intracardiac shunt. We report epidural anesthesia with evaluation of echocardiography during anesthesia in a patient with Ebstein’s malformation. A 58-yr-old woman underwent emergent repair for left foot joint fracture. The Ebstein’s malformation had been found at 42 yr of age, but no right-left shunt was found at that time. Echocardiography revealed downward displacement of the tricuspid valve but no right-to-left shunts. We estimated cardiac function using echocardiography from the start of anesthesia. After spinal anesthesia was induced with 0.5% bupivacaine (10 mg), the epidural catheter was introduced to the epidural space via the L4-5 space. A total dose of 11 mL of mepivacaine 1% produced analgesia from S5 to T11. Arterial blood pressure and heart rate did not change with anesthesia and Spo2 also remained at 100%. The right ventricle diastolic diameter before and after anesthesia was 2.9 cm and 3.0 cm, respectively (Figures 1 and 2). During surgery, we continued observing the right ventricle diastolic diameter to avoid excessive administration of IV fluids. Total fluid was 700 mL. During and after anesthesia, her vital signs did not change to any clinical significant degree. Hazards during anesthesia include development of cardiac tachydysrhythmias and hypoxemia as the result of increases in the magnitude of the right-to-left intracardiac shunts. Several anesthetic managements in patients with Ebstein’s malformation have been described (1–4). General anesthesia has the advantage that hypotension tends to be avoided, but arrhythmia and tachycardia may occur after intubation and extubation of the trachea. In contrast, Linter and Clarke (2) showed the successful use of a two-catheter technique for elective Cesarean delivery with extradural analgesia. Epidural or spinal anesthesia may be appropriate in non-severe patients, but excessive administration of fluid should be avoided because it may increase right arterial pressure sufficiently to cause an increased right-to-left shunt and hypoxemia. In this anesthesia, we evaluated cardiac preload and function using echocardiography. Although central venous pressure monitoring or the insertion of a pulmonary artery catheter may be useful to evaluate cardiac preload, these measures may be technically difficult in Ebstein’s anomaly and lead to complications such as tachyarrhythmias or paradoxical emboli. Transesophageal echocardiography may be also useful, but it would be difficult to monitor in our case for an extended period because the patient was awake during surgery. Echocardiography is and noninvasive and can be used frequently. It provides much information about changes of the cardiovascular system, especially for this patient with Ebstein’s malformation even during anesthesia. In conclusion, epidural or spinal anesthesia may be appropriate in nonsevere patients and echocardiography should be useful monitoring during anesthesia for patients with Ebstein’s malformation.

References 1 Gleicher N, Meller J, Sandler RZ, Sullum S. WolffParkinson-White syndrome in pregnancy. Obstet Gynecol 1981; 58: 748–52. 2 McKenna WJ, Harris L, Rowland E, Whitelaw A, Storey G, Holt D. Amiodarone therapy during pregnancy. Am J Cardiol 1983; 51: 1231–3. 3 Oberoi GS, Yaubihi N. Anaesthesia for caesarean section in a patient with Wolff-Parkinson-White syndrome. PNG Med J 1991; 34: 65–8.

To the Editor: Sometimes, intubation with a double-lumen tube (DLT) is difficult. We present a patient who was ventilated after esophageal intubation with a DLT used like an esophageal-endotracheal combitube (EEC). A 66-yr-old female patient (155 cm, 74 kg, body mass index = 31) was scheduled for thymectomy for gradeI myasthenia gravis. Her thyromental distance was less than 6 cm and difficult intubation was predicted. General anesthesia was induced with 70 mg propofol and 0.1 mg fentanyl, and maintained with 4% sevoflurane. She was intubated without using a muscle relaxant with a 35 Fr-Left-DLT (Sheridan, Tyco, Tokyo, Japan). Her Cormack's laryngoscopic view was grade 3. Although the DLT could not be advanced more than 21 cm from the patient's incisors, endotracheal intubation was assumed when spontaneous breathing re-appeared rapidly and capnography detected a normal CO2 waveform. However, the patient could not be ventilated mechanically. Subsequent fibroscopy via the bronchial lumen revealed esophageal intubation. The bronchial lumen compressed the posterior wall of the esophageal inlet, while the tracheal lumen opened just posterior to the arytenoid cartilages (Figure). In this case, the DLT performed as an EEC. Grmec reported that capnography was the most reliable method to confirm esophageal intubation,1 since the CO2 waveform generally decreases to zero, even if an initial pulse of swallowed CO2 is sensed. However, repeated airway evaluations should be performed to prevent a misdiagnosis such as occurred in our case, rather than depending on capnography alone.