Takuya Miyawaki

Dexmedetomidine enhances the local anesthetic action of lidocaine via an α-2A adrenoceptor

BACKGROUND: Clonidine, an &agr;-2 adrenoceptor agonist, is a common adjunct in both central and peripheral blocks. Dexmedetomidine, a more selective &agr;-2 adrenoceptor agonist, is also known to enhance central neural blockades. Its peripheral effect, however, has not been fully elucidated. Thus, we evaluated the effect of dexmedetomidine and other &agr;-2 adrenoceptor agonists on the local anesthetic action of lidocaine at the periphery and explored the mechanism involved. METHODS: &agr;-2 Adrenoceptor agonists, including dexmedetomidine, clonidine, and oxymetazoline, combined with lidocaine were intracutaneously injected into the back of male guinea pigs. The test of six pinpricks was applied every 5 min until 60 min after the injection. The number of times which the prick failed to elicit a response during the 60-min period was added and the sum served as an anesthetic score indicating the degree of local anesthesia. Differences from the control value within the group were analyzed using an analysis of variance followed by a post hoc Dunnett’s test. Furthermore, we evaluated the antagonism of the effect of dexmedetomidine by yohimbine, an &agr;-2A, 2B, and 2C adrenoceptor antagonist, or prazosin, an &agr;-1, &agr;-2B, and 2C adrenoceptor antagonist, analyzed using a two-way analysis of variance. RESULTS: All &agr;-2 adrenoceptor agonists enhanced the degree of local anesthesia of lidocaine in a dose-dependent manner. Furthermore, yohimbine inhibited the effect of dexmedetomidine, whereas prazosin did not. CONCLUSION: We demonstrated that &agr;-2 adrenoceptor agonists enhanced the local anesthetic action of lidocaine, and suggest that dexmedetomidine acts via &agr;-2A adrenoceptors.

Elevation of plasma interleukin-6 level is involved in postoperative fever following major oral and maxillofacial surgery

OBJECTIVE The purpose of this study was to evaluate whether the changes in plasma cytokine levels including interleukin-6 (IL-6) interleukin-1 beta (IL-1 beta), and tumor necrosis factor-alpha (TNF-alpha) are involved in postoperative fever following oral and maxillofacial surgery. STUDY DESIGN Ten patients undergoing elective oral and maxillofacial surgery were studied. We investigated the plasma cytokine levels by using an enzyme-linked immunosorbent assay and measured the core temperature and degree of postoperative shivering and peripheral vasoconstriction after surgery. The relationships between the changes in plasma cytokine levels and postoperative fever were statistically evaluated using Spearmans rank correlation coefficients. RESULTS The elevation of plasma IL-6 level was significantly correlated with the increase in core temperature after surgery and with the degree of postoperative shivering and vasoconstriction, whereas the changes in plasma II-1 beta or TNF-alpha levels were not. CONCLUSIONS Elevation of plasma IL-6 level is probably involved in postoperative fever following oral and maxillofacial surgery.

Heme oxygenase-1 induction in the brain during lipopolysaccharide-induced acute inflammation

Delirium occurs in 23% of sepsis patients, in which pro-inflammatory cytokines and nitric oxide are suggested to be involved. However, in animal experiments, even a subseptic dose of lipopolysaccharide (LPS) injection induces both pro-inflammatory cytokines and inducible nitric oxide synthase in the brain, suggesting that the brain oxidative reaction can be induced in the subseptic condition. Then, we evaluated the changes of heme oxygenase-1 (HO-1), a sensitive oxidative marker, as well as interleukin (IL)-1β, IL-6, and inductible nitric oxide synthase (iNOS) mRNA in the hypothalamus and hippocampus of rats using real-time PCR after peripheral injection of LPS (2.0 mg/kg). As a result, these four kinds of mRNAs were induced significantly in both areas after LPS injection. These results suggest that peripheral inflammation induces an oxidative reaction in the brain, even if the inflammation is not lethal. It is also considered that several pathways are involved in brain HO-1 induction.

Propofol suppresses a hyperpolarization-activated inward current in rat hippocampal CA1 neurons

We examined the effect of propofol and thiopental, intravenous anesthetics, on the hyperpolarization-activated inward current (I(H)), whose functional role on the neuronal activity has been evaluated. Whole-cell recordings of I(H) evoked by hyperpolarizing step pulses were taken from hippocampal CA1 neurons in rat brain slices. Propofol reduced I(H) current in a dose-dependent manner. However, thiopental had no significant effect on the activation of I(H). According to the functional role of I(H), the suppression of I(H) should result in a reduction of neuronal activity. We suggest that the effectiveness of propofol as an anticonvulsant or an antiemetic is associated with the blockade of the I(H) channel.

Ketamine and midazolam differentially inhibit nonadrenergic noncholinergic lower esophageal sphincter relaxation in rabbits: role of superoxide anion and nitric oxide synthase.

Background The authors previously reported that ketamine and midazolam inhibited nitric oxide-mediated nonadrenergic noncholinergic (NANC) lower esophageal sphincter (LES) relaxation via nitric oxide-3′,5′-cyclic guanosine monophosphate pathway modulation. The mechanisms inhibiting the NANC relaxation by ketamine and midazolam were investigated. Methods The isometric tension of circular distal esophageal muscle strips from Japanese White rabbits was examined. NANC relaxation was induced by KCl (30 mm) in the presence of atropine (3 × 10−6 m) and guanethidine (3 × 10−6 m). Nitric oxide synthase activity in the absence and presence of ketamine and midazolam was analyzed using the biochemical conversion of L-[3H]arginine to L-[3H]citrulline. Results The ketamine-induced inhibition of the NANC relaxation was partly reversed by superoxide dismutase (200, 400 U/ml) but not by catalase (100 U/ml). Ketamine concentration-dependently inhibited the relaxation induced by N-ethylethanamine:1,1-diethyl-2-hydroxy-2-nitrosohydrazine (diethylamine NONOate) and S-nitrosoglutathione. The NANC relaxation itself was not affected by superoxide dismutase. The midazolam-induced inhibition of the NANC relaxation was reversed neither by superoxide dismutase nor by catalase, and midazolam did not affect the relaxations induced by nitric oxide donors. The nitric oxide synthase activity was concentration-dependently suppressed by midazolam, but there was no marked effect of ketamine. Pyrogallol, a superoxide generator, inhibited the NANC and the diethylamine NONOate-induced relaxations. The pyrogallol-induced inhibition of the NANC relaxation was reversed by superoxide dismutase. Conclusion These findings suggest that ketamine inhibits NANC LES relaxation by the extracellular production of superoxide anion, and that midazolam inhibits it by the inhibition of nitric oxide synthase activity.

Effect of intravenous infusion of a β-adrenergic blocking agent on the haemodynamic changes in human masseter muscle induced by cold-pressor stimulation

Eight healthy non-smoking males (mean age: 24.1 +/- 1.1 years) without any history of chronic muscle pain and migraine participated in this study. Haemoglobin (Hb) and oxygen (O2) saturation in the right masseter muscle were continuously recorded with a non-invasive near-infrared spectroscopic device. Heart rate and blood pressure were also recorded. The experiment had three phases: a placebo drug (physiological saline) with cold-pressor trial, a 30-sec maximal voluntary clenching (MVC) trial, and a propranolol with cold-pressor trial. The saline and drug trials each involved continuous recording for 1 min before, 2 min during and 5 min after the cold-pressor stimulation (4 degrees C). Physiological saline (20 ml) or propranolol hydrochloride (20 ml) were infused at the rate of 2 ml/min. This infusion was begun 20 min before the baseline recording and participants did not know which solution (saline or propranolol) was being infused. For the MVC trial, each participant was asked to perform a 30-sec clench of their jaw-closing muscles. There was a rest period of 15 min between each trial. The individual Hb and O2 data were normalized so that the baseline at the beginning of the experiment was equal to zero, and the Hb and O2 data were normalized as a percentage of the individuals own highest absolute Hb and O2 after and during the MVC, respectively. The results showed that the mean baseline Hb 1 min before cold-pressor stimulation was significantly lower in the beta-blocker trial than in the placebo trial (p = 0.035). The mean change in Hb from baseline during cold-pressor stimulation in the beta-blocker trial was also significantly less than in the placebo trial (p = 0.035). The mean Hb rebound change after the cold-pressor stimulation in the beta-blocker trial was significantly higher than in the placebo trial, and no significant heart-rate differences were observed in the period after cold-pressor stimulation. Overall, the mean heart rate before and during that stimulation was significantly lower in the beta-blocker trial than the placebo trial (p < 0.001). There was no significant mean blood-pressure difference between placebo and beta-blocker trials at any time. These results suggest that beta-adrenoceptor blocking decreases the blood volume in the resting masseter, suppresses the incremental blood-volume change during cold-pressor stimulation, and discloses a hidden vasoconstrictive effect after that stimulation.

Locally Injected Dexmedetomidine Inhibits Carrageenin-induced Inflammatory Responses in the Injected Region

BACKGROUND:Dexmedetomidine, a highly selective agonist of &agr;2-adrenoceptors, is a commonly used sedative; however, a potent anti-inflammatory effect has also been found. In the present study we evaluated the inhibitory effect of locally injected dexmedetomidine on inflammatory responses in the injected region. METHODS:Local inflammation was induced in the hindpaws of male mice (aged 6–8 weeks) by intraplantar injection of lambda-carrageenin. To offset the central effect of tested agents, different agents were blindly injected into the left and right paws in the pairs of comparison. The effect of dexmedetomidine on edema (increase in paw volume), the accumulation of leukocytes, and production of tumor necrosis factor-&agr; (TNF-&agr;) and cyclooxygenase-2 (COX-2) were evaluated after carrageenin injection, using water displacement plethysmometry, histological imaging, immunohistochemistry, and Western blotting analysis. Furthermore, we also evaluated the effect of yohimbine, a full antagonist of &agr;2-adrenoceptors, and phenylephrine, an agonist of the &agr;1-adrenoceptor, on dexmedetomidine’s action on inflammatory responses. RESULTS:Paw volume and amount of leukocytes in the injected region significantly increased after the injection of carrageenin. Similarly, TNF-&agr; and COX-2 production was found in the subcutaneous region injected with carrageenin, 4 hours after injection. Dexmedetomidine significantly inhibited all increases in paw volume, leukocytes, and production of TNF-&agr; and COX-2. Furthermore, yohimbine significantly antagonized the anti-inflammatory effects of dexmedetomidine, whereas phenylephrine did not significantly alter them. CONCLUSIONS:The findings suggest that locally injected dexmedetomidine exhibits an anti-inflammatory effect against local acute inflammatory responses, mediated by &agr;2-adrenoceptors.

The influence of oral VPA on the required dose of propofol for sedation during dental treatment in patients with mental retardation: A prospective observer-blinded cohort study

In sedation of dental patients with moderate or severe mental retardation, it is difficult to identify the optimum sedation level and to maintain it appropriately. Moreover, many patients have concomitant epilepsy and are medicated with oral antiepileptic drugs (AEDs), which influence the drug‐metabolizing enzymes. In particular, valproate (VPA) has been demonstrated to inhibit propofol metabolism in vitro. Therefore, the objective of the present study was to investigate the clinical influence of oral VPA on the required dose of propofol for sedation, with use of a prospective cohort study design. We studied 45 patients with moderate or severe mental retardation who underwent dental treatment under sedation. Propofol was infused, and sedation was maintained at the same level in all patients using a bispectral index (BIS) monitor. After the completion of treatment for the scheduled patients, patients were divided into those with oral VPA treatment (VPA group: 20 patients) and without any oral antiepileptic treatment (control group: 25 patients). The propofol dose required for sedation and times to the recovery of the eyelash reflex and spontaneous eye opening were evaluated. The median required propofol doses in the VPA and control groups were 4.15 (range 1.97–5.88) and 5.67 (2.92–7.17) mg/kg/h, respectively. We observed a statistically significant difference between the two patient groups with respect to median VPA dose (p < 0.01). However, no statistically significant differences were noted in the time until eyelash reflex recovery or spontaneous eye opening between the two groups. The results suggest that oral VPA reduces the dose of propofol required for sedation during dental treatment in patients with moderate or severe mental retardation.

Dental Sedation for Patients with Intellectual Disability：A Prospective Study of Manual Control versus Bispectral Index-Guided Target-Controlled Infusion of Propofol

STUDY OBJECTIVE To investigate the use of propofol sedation using Bispectral Index (BIS)-guided target-controlled infusion (TCI) in dental patients with intellectual disability. DESIGN Single-center, prospective, randomized clinical trial. SETTING Academic outpatient clinic. SUBJECTS 40 ASA physical status 1 and 2 patients with intellectual disability. INTERVENTIONS Patients were randomized to two groups. The manual control (MC) group (n = 20) had sedation by manually controlled infusion of propofol without a BIS index monitor. The BIS-TCI group (n = 20) had sedation by BIS-guided TCI of propofol. MEASUREMENTS The required dose of propofol, recovery time for the eyelash reflex, and spontaneous eye opening times were recorded. MAIN RESULTS BIS-TCI significantly reduced the dose of propofol and shortened the recovery times for eyelash reflex and spontaneous eye opening. CONCLUSION Propofol sedation using BIS-guided TCI is a useful and safe method in the management of patients with intellectual disability.

Peripheral N-Methyl-D-Aspartate Receptors Modulate Nonadrenergic Noncholinergic Lower Esophageal Sphincter Relaxation in Rabbits

We investigated the role of peripheral N-methyl-d-aspartate (NMDA) receptors in the myenteric plexus in mediating nonadrenergic noncholinergic (NANC) nitrergic relaxation of the lower esophageal sphincter (LES). Isometric contraction of LES strips from Japanese White rabbits was measured. NANC relaxation was induced by KCl (30 mM) in the presence of atropine and guanethidine. The concentration of 3′,5′-cyclic guanosine monophosphate (cGMP) was measured using a radioimmunoassay. The muscle strips were exposed to diethyldithiocarbamic acid (DETCA; 3 mM) to inactivate Cu/Zn superoxide dismutase. MK801 (5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)cyclohepten-5,10-imine) inhibited NANC relaxation in a concentration-dependent manner (EC50 = 1.5 × 10−5 M), accompanied by a decrease in cGMP production. NMDA induced a concentration-dependent relaxation, which was antagonized by MK801. NMDA stimulated cGMP production, which was inhibited by NG-nitro-l-arginine. Superoxide dismutase (100 U/mL) shifted the concentration-response relationship of MK801-mediated inhibition of NANC relaxation to the right (EC50 = 3.4 × 10−5 M), whereas catalase did not. Treatment with DETCA shifted the concentration-response relationships of pyrogallol-, ketamine- and MK801-mediated inhibition of NANC relaxation to the left. These findings suggest that the peripheral NMDA receptors mediate NANC smooth muscle relaxation, and modulate it, in part, through extracellular production of superoxide anions, thus eliminating the relaxant effect of endogenous nitric oxide.