Tetsutaro Shinomura

Nitric Oxide Synthase Inhibitor Does Not Reduce Minimum Alveolar Anesthetic Concentration of Halothane in Rats

Nitric oxide (NO) synthase inhibitor (Nω-nitro-L-arginine methyl ester [L-NAME]) has been reported to reduce minimum alveolar anesthetic concentration (MAC) of halothane when administered intravenously (IV) and to reduce thermal hyperalgesia, or produce antinociception in the formalin test, when administered intracerebroventricularly (ICV) or intrathecally (IT). This study attempts to identify the site(s) in the central nervous system (CNS) where L-NAME acts to reduce the halothane MAC. For this purpose, we examined the effects of IV, ICV, and IT administration of L-NAME on the halothane MAC in rats. In contrast to an earlier study, we did not observe any decrease in the halothane MAC after IV (10–30 mg/kg) administration of L-NAME. ICV (100 pg) and IT (100 pg and 1 mg) administration of L-NAME also did not alter the halothane MAC. These findings indicate that the L-arginine-NO pathway is not involved in the mechanism of action of halothane to suppress mechanical nociceptive response or in the nociceptive neural mechanism of mechanical stimulation.

Reduction of depolarization-induced glutamate release by heme oxygenase inhibitor: Possible role of carbon monoxide in synaptic transmission

The effects of carbon monoxide on the release of glutamate were studied in synaptoneurosomal preparations using a fluorometric system. Zinc protoporphyrin IX, an inhibitor of the heme oxygenase that produces carbon monoxide, reduced depolarization-induced glutamate release in a calcium-dependent manner, but had no effect on calcium-independent glutamate release. On the basis of this finding, we suggest that carbon monoxide plays a pivotal role in glutamate release in synapses, and may be a retrograde messenger in long-term potentiation.

Chronic Treatment with Nitric Oxide Synthase (NOS) Inhibitor Profoundly Reduces Cerebellar NOS Activity and Cyclic Guanosine Monophosphate but Does Not Modify Minimum Alveolar Anesthetic Concentration

We previously found that acute administration of a nitric oxide synthase (NOS) inhibitor (Nomega-nitro-L-arginine methyl ester [L-NAME]) does not reduce the minimum alveolar anesthetic concentration (MAC) of halothane in rats. However, a recent study has suggested that brain NOS activity could not be inhibited by more than approximate equals 50% by acute administration of L-NAME. To investigate the effect of marked inhibition of NOS activity on the MAC of halothane, we measured cerebellar NOS activity, cerebellar cyclic guanosine monophosphate (cGMP) levels, and halothane MAC in rats chronically treated with L-NAME and compared the results to those of the saline-treated control group. Although the cerebellar NOS activity and cGMP levels were significantly decreased (14% and 2.7% of control, respectively) by L-NAME, the value of the halothane MAC was not significantly affected. These results suggest that the anesthetic action of halothane, as measured by its MAC in rats, is not related to NOS activity or cGMP levels in the brain. (Anesth Analg 1995;81:862-5)

Halothane and Diazepam Inhibit Ketamine-induced c-fos Expression in the Rat Cingulate Cortex

Background Ketamine, a noncompetitive N‐methyl‐D‐aspartate antagonist, has psychotomimetic side effects. Recent studies have shown that noncompetitive N‐methyl‐D‐aspartate antagonists cause morphologic damage to the cingulate and retrosplenial cortices and induce c‐fos protein (c‐Fos) in the same regions. Although benzodiazepines are effective in preventing these side effects, the neural basis of the drug interactions has not been established. Methods The effects of diazepam and halothane on c‐Fos expression induced by ketamine were studied. Diazepam (1 and 5 mg/kg) or vehicle were administered subcutaneously, followed 7 min later by 100 mg/kg ketamine given intraperitoneally. Halothane (1.0 and 1.8%), was administered continuously from 10 min before ketamine administration until brain fixation. Two hours after ketamine injection, rats were perfused and their brains fixed and extracted. Brain sections were prepared in a cryostat and c‐Fos expression was detected using immunohistochemical methods. Results Ketamine induced c‐Fos‐like immunoreactivity in the cingulate and retrosplenial cortices, thalamus, and neocortex. Diazepam suppressed the ketamine‐induced c‐Fos‐like immunoreactivity in the cingulate and retrosplenial cortices in a dose‐dependent manner, leaving the thalamus and neocortex less affected. Halothane suppressed the ketamine‐induced c‐Fos‐like immunoreactivity in the cingulate and retrosplenial cortices and the neocortex in a dose‐dependent manner, leaving the thalamus relatively unaffected. Conclusion Halothane and diazepam inhibited ketamine‐induced c‐Fos expression in the cingulate and retrosplenial cortices, leaving the thalamus relatively unaffected.

Effects of isoflurane on in vivo release of acetylcholine in the rat cerebral cortex and striatum.

Background: Acetylcholine (ACh) is one of the major excitatory neurotransmitters in the central nervous system, and changes in neural activity induced by anesthesia alter the release of ACh. However, the effects of isoflurane, one of the most widely used volatile anesthetics, on ACh release are not known. The present study attempts to clarify the dose–effect relationship of isoflurane on the in vivo release of ACh in rat brains.

Clonidine inhibits and phorbol acetate activates glutamate release from rat spinal synaptoneurosomes.

UNLABELLED Glutamate is a major neural transmitter of noxious stimulation in the spinal cord. We measured glutamate release from rat spinal synaptoneurosomes by using an enzyme-linked fluorimetric assay. Glutamate was released from spinal cord synaptoneurosomes in response to the addition of 30 mM potassium chloride, 1 mM 4-aminopyridine, or 1 microM ionomycin in the presence of external calcium. There was less release of glutamate in the absence, versus the presence, of external calcium. Clonidine significantly reduced the level of glutamate released from the spinal cord synaptoneurosomes. Tetradecanoyl phorbol acetate, an activator of protein kinase C, enhanced glutamate release. Forskolin, a protein kinase A activator, had no effect on the glutamate efflux. Our data indicate that glutamate released in the spinal cord is dependent on protein kinase C but is independent of the protein kinase A pathway. They also suggest that the inhibition of glutamate release may be the underlying mechanism of antinociception by clonidine at the spinal cord level. IMPLICATIONS We demonstrated that synaptoneurosomes from rat spinal cord could release glutamate in response to depolarization. We showed that an activator of protein kinase C increased glutamate released from spinal cord synaptoneurosomes but that clonidine decreased it. Glutamate release may be one of the mechanisms of antinociception at the spinal cord level.

Compound A concentration is decreased by cooling anaesthetic circuit during low-flow sevoflurane anaesthesia

PurposeIn the presence of carbon dioxide absorbents, sevoflurane is degraded to CF2=C(CF3)OCH2F, an olefin compound A. There remains some concern of the hepatic and renal toxicity that compound A poses when using low-flow anaesthetic techniques. We investigated a device to decrease the concentration of compound A products by decreasing the temperature of exhaled air and soda lime in semi-closed low-flow anaesthesia technique in surgical patients.MethodsTen patients, ASA 1 or 2, were studied. Five received anaesthesia using a cooling circuit, that consisting of an anaesthetic circuit and an intercooler device interposed in the expiratory tube. The intercooler was dipped in an iced water tank. Anaesthesia was given through this circuit from induction to emergence. Another five patients received anaesthesia without cooling. Anaesthesia was maintained with sevoflurane and O2 50%/N2O during four to six hours of operation. A fixed concentration of sevoflurane 2% at a total flow of 1 L·min−1 was administered. Gas samples were taken every hour and compound A was quantitated by gas chromatography. The temperatures of canister, circuit and body were measured every hour.ResultsThe device effectively lowered the temperatures [24 ± 3.4 to 5 ± 1,3°C] and the concentrations of compound A [27.1 ± 3.8 ppm to 16.3 ± 2.08 ppm,P < 0.05] in the circuit. The body temperatures were not lowered.ConclusionCompound A concentrations were reduced by cooling the anaesthetic circuit in clinical settings.ObjectifEn présence d’absorbants du gaz carbonique, le sévoflurane se dégrade en CF2=C(CF3)OCH2F, un composé oléfine A. Ce qui nous fait toujours craindre une certaine toxicité hépatique et rénale possible lors de l’emploi de techniques anesthésiques à débit lent. Nous avons fait l’essai d’un dispositif qui diminuerait la concentration du composé A en abaissant la température de l’air expiré et de la chaux sodée dans un circuit anesthésique semi-fermé à débit lent.MéthodeDix patients, ASA I ou II, ont été étudiés. Cinq d’entre eux ont reçu une anesthésie avec l’emploi d’un appareil refroidisseur interposé sur le tube d’expiration du circuit d’anesthésie. Le refroidisseur était plongé dans un réservoir d’eau glacée. L’anesthésie a été administrée par ce circuit depuis l’induction jusqu’au réveil. Les cinq autres patients ont reçu une anesthésie sans refroidissement. Lanesthésie a été maintenue avec du sévoflurane et un mélange d’O2 et de N2O à 50 % pendant les quatre à six heures de l’intervention. Une concentration fixe de 2 % de sévoflurane à un débit total de 1 L·min−1 a été administrée. Des échantillons de sang ont été prélevés à chaque heure et le composé A a été mesuré par Chromatographie en phase gazeuse. Les températures de la chaux, du circuit et du corps ont été mesurées à chaque heure.RésultatsLe dispositif a efficacement réduit les températures [de 24 ± 3,4 à 5 ± 1,3°C] et les concentrations du composé A [de 27,1 ± 3,8 ppm à 16,3 ± 2,08 ppm,P < 0,05] dans le circuit. La température du corps n’a pas baissé.ConclusionLes concentrations de composé A ont été réduites par le refroidissement du circuit anesthésique en pratique clinique.

Compound A concentration and the temperature of CO2 absorbents during low-flow sevoflurane anesthesia in surgical patients.

Sevoflurane, a new inhalational anesthetic, is metabolically broken down into several decomposition products in the presence of CO2 absorbents. One of the products, CF2=C (CF3) OCH2F (compound A), which appears to be the most toxic, was quantitated in 20 surgical patients subjected to more than 3 h of anesthesia using a low-flow anesthesia circuit. To minimize the variables in the reaction velocity between sevoflurane and the CO2 absorbents, we maintained the sevoflurane concentration at 2%. Wakolime-A, one type of soda lime, resulted in the highest increase in compound A concentration. The peak concentration was 27.1±3.1 ppm, less than one-tenth of the LC50 (50% lethal concentration) of compound A, which was previously reported as 420 or 400 ppm in rats. We also measured the temperature in CO2 absorbents, which had been reported to influence compound A production. The elevation in the temperature was 27.9±1.3°C in Wakolime-A, 29.4±8.4°C in Baralyme, and 31.0±5.0°C in Sodasorb II. Further studies are needed to assess the safety and efficacy of sevoflurane.

Effect of hypercapnia on arterial hypotension after induction of anaesthesia

We evaluated the effectiveness of intentional hypercapnia against hypotension after induction of anaesthesia with thiopental and isoflurane (TI) or propofol (P). For each group, 24 patients were anaesthetized with thiopental 4 mg kg−1 (TI) or propofol 2 mg kg−1 (P) for tracheal intubation and then lightly anaesthetized with isoflurane at 0.6% end‐expiratory concentration (TI) or by 6 mg kg−1 h−1 infusion of propofol (P). In both anaesthesia groups, patients were randomly assigned to either normocapnia (end‐tidal CO2 = 35 mmHg) or hypercapnia (end‐tidal CO2 = 45 mmHg), which were achieved through adjusting the tidal volume. Systolic arterial pressure (SAP) 15 min after intubation was compared with the preanaesthetic baseline value. Under normocapnia, both TI and P induced a comparable, statistically significant suppression of SAP by approximately 20 mmHg from baseline. Hypercapnia prevented the decrease in SAP in TI but not in P. No patient in the TI‐hypercapnia group experienced SAP below 100 mmHg, unlike those in the other groups. In conclusion, mild hypercapnia was effective in the prevention of hypotension in patients receiving thiopental followed by 0.6% end‐expiratory isoflurane, but not in patients receiving 6 mg kg−1 h−1 propofol.

Anesthesia management for emergency laparotomy in a pediatric patient with suspected hereditary angioedema.

Hereditary angioedema (HAE) is caused by complement factor 1 inhibitor (C1-INH) deficiency, and its mode of inheritance is autosomal dominant. We present a case of an 8-year-old patient who required emergency laparotomy after a traffic accident. General anesthesia with tracheal intubation was necessary. The patient’s mother and maternal grandmother had been diagnosed with HAE. HAE is associated with high mortality when airway edema is caused by tracheal intubation. It was impossible to rule out HAE preoperatively in the patient. Therefore, we presumed that he had HAE and treated him with pasteurized C1-INH concentrate. The patient underwent laparotomy uneventfully. Several days after the operation, the laboratory data revealed that the perioperative plasma complement 1 q subunit (C1q) protein level and C1-INH function were not lowered. The diagnosis of HAE was not confirmed, but it was not possible to rule out the diagnosis either. The prophylactic use of a C1-INH in this case may be justified, because the procedure was an emergency and because of the high mortality associated with tracheal intubation in patients with HAE.