Masahiro Kakuyama

Mechanisms of inhibition of endothelium-dependent relaxation by halothane, isoflurane, and sevoflurane.

Volatile anaesthetics inhibit endothelium-dependent relaxation, but the underlying mechanism(s) have not been clarified. In an attempt to elucidate the mechanism(s), we determined the effects of halothane, isoflurane and sevoflurane on relaxation induced by acetylcholine and sodium nitro-prusside (SNP) and the cGMP formation elicited by exogenous nitric oxide (NO) and SNP in rat aortas. Acetylcholine (10−7−10−5M) - induced relaxation was attenuated by halothane (2%), isoflurane (2%) and sevoflurane (4%). SNP (10−8 M) - induced relaxation was reduced by halothane (2%), but not by isoflurane (2%) or sevoflurane (4%). The cGMP level of NO-stimulated aorta was reduced by halothane (2%) and sevoflurane (4%), but not by isoflurane (2%). The cGMP level of SNP (10−7 M) - stimulated aorta was reduced by halothane (2%), but not by isoflurane (2%) and sevoflurane (4%). We conclude that the mechanisms responsible for the inhibition of endothelium-dependent relaxation differ among anaesthetics. Isoflurane inhibits the relaxation mainly by inhibiting the formation of NO in the endothelium. In contrast, the effect of halothane on endotheliumdependent relaxation may be largely due to the inhibition of action of NO in the vascular smooth muscle and the effect of sevoflurane may be to inactivate NO or to inhibit the action of NO.RésuméLes agents anesthésiques volatils inhibent la relaxation d’origine endothéliale dont le mécanisme sous-jacent n’a pas été éclairci. Dans le but d’en élucider le(s) mécanisme(s), nous avons déterminé sur des aortes de rats les effets de l’halothane, de l’isoflurane et du sévoflurane sur la relaxation induite par l’acétylcholine et le nitroprussiate de sodium (SNP), et la synthèse de cGMP élicitée par l’oxyde nitrique (NO) et le SNP La relaxation induite par l’acétylcholine (10−7−10−5 M) est atténuée par l’halothane 2%, l’isoflurane 2% et le sévoflurane 4%. La relaxation induite par le SNP (10−8 M) est diminuée par l’halothane 2%, mais non par l’isoflurane 2% ou le sévoflurane 4%. Le niveau de cGMP de l’aorte stimulée par le NO est diminué par l’halothane 2% et le sévoflurane 4% mais non par l’isoflurane 2%. Le niveau de cGMP de l’aorte stimulée par le SNP (10−7) est diminué par l’halothane 2%, mais non par l’isoflurane 2% et le sévoflurane 4%. Nous concluons que les mécanismes responsables de l’inhibition de la relaxation d’origine endothéliale different selon l’anesthésique. L’isoflurane inhibe la relaxation principalement en inhibiant la synthèse endothéliale de NO. Par contre, l’effet de l’halothane sur la relaxation d’origine endothéliale peut être en grande partie due à l’inhibition de l’activité du NO sur le muscle vasculaire lisse et l’effet du sévoflurane peut être dû à l’inactivation du NO ou à l’inhibition de l’activité du NO.

Halothane and isoflurane inhibit endothelium-dependent relaxation elicited by acetylcholine

The purpose of this study was to determine whether volatile anesthetics modify the release of endothelium-derived relaxing factor. We examined the effects of halothane and isoflurane on endothelium-dependent relaxation and 3′,5′-cyclic guanosine monophosphate formation elicited by acetylcholine and ionophore A23187 in isolated rat aorta. Halothane and isoflurane (1%--2%) significantly attenuated acetylcholine-induced relaxation of the phenylephrine-contracted aorta but had no significant effect on relaxation induced by A23187, nitroprusside, and nitroglycerin. Basal and A23187 (10−7 M)-stimulated levels of 3′,5′-cyclic guanosine monophosphate were slightly lowered by halothane and isoflurane (2%). In contrast, the increase of 3′, 5′-cyclic guanosine monophosphate elicited by acetylcholine (10−5 M) was significantly attenuated by halothane (2%) and abolished by isoflurane (2%). These findings indicate that halothane and isoflurane strongly inhibit the release of endothelium-derived relaxing factor elicited by acetylcholine.

Modification of Endothelium-dependent Relaxation by Propofol, Ketamine, and Midazolam

Since volatile anesthetics, barbiturates, and local anesthetics have been reported to inhibit endothelium-dependent relaxation, we hypothesized that any drug with anesthetic action would suppress this relaxation. In the present study, using rat thoracic aortae, we attempted to determine whether nonbarbiturate intravenous anesthetics, including midazolam, propofol, and ketamine, suppress endothelium-dependent relaxation, and to clarify the mechanism(s) involved. Acetylcholine-induced, endothelium-dependent relaxation was significantly attenuated by propofol and ketamine, but was unaffected by midazolam. Sodium nitroprusside (SNP)-induced relaxation was attenuated by propofol, but not by midazolam or ketamine. The acetylcholine-stimulated 3 prime,5 prime-cyclic guanosine monophosphate (cGMP) level was reduced by pretreatment with propofol and ketamine but not by midazolam, and that stimulated by SNP was reduced by propofol but not by ketamine or midazolam. We conclude that propofol and ketamine suppress endothelium-dependent relaxation, whereas midazolam has no influence. Moreover, the suppressive effect of ketamine on endothelium-dependent relaxation is mediated by suppression of nitrous oxide (NO) formation, whereas that of propofol may be mediated at least partly by suppression of NO function. (Anesth Analg 1995;81:474-9)

“Deep-forehead” temperature correlates well with blood temperature

Purpose: To evaluate the accuracy and precision of “deep-forehead” temperature with rectal, esophageal, and tympanic membrane temperatures, compared with blood temperature.Methods: We studied 41 ASA physical status 1 or 2 patients undergoing abdominal and thoracic surgery scheduled to require at least three hours. “Deep-forehead” temperature was measured using a Coretemp® thermometer (Terumo, Tokyo, Japan). Blood temperature was measured with a thermistor of a pulmonary artery. Rectal, tympanic membrane, and distal esophageal temperatures were measured with thermocouples. All temperatures were recorded at 20 min intervals after the induction of anesthesia. We considered blood temperature as the reference value. Temperatures at the other four sites were compared with blood temperature using correlation, regression, and Bland and Altman analyses. We determined accuracy (mean difference between reference and test temperatures) and precision (standard deviation of the difference) of 0.5°C to be clinically acceptable.Results: “Deep-forehead” temperature correlated well with blood temperature as well as other temperatures, the determination coefficients (r2) being 0.85 in each case. The bias for the “deep-forehead” temperature was 0.0°C which was the same as tympanic membrane temperature and was smaller than rectal and esophageal temperatures. The standard deviation of the differences for the “deep-forehead” temperature was 0.3°C, which was the same as rectal temperature.Conclusions: We have demonstrated that the “deep-forehead” temperature has excellent accuracy and clinically sufficient precision as well as other three core temperatures, compared with blood temperature.RésuméObjectif: Évaluer l’exactitude et la précision de la température frontale «cutanée profonde» et les températures rectale, œsophagienne et tympanique, comparées à la température du sang.Méthode: L’étude a porté sur 41 patients d’état physique ASA I ou II devant subir une intervention chirurgicale abdominale et thoracique d’au moins deux heurs. La température «cutanée profonde» a été mesurée à l’aide du thermomètre Coretemp® (Terumo, Tokyo, Japon). Celle du sang a été prise avec une thermistance d’une artère pulmonaire et les températures rectale, tympanique et œsophagienne distale, avec des thermocouples. Elles ont toutes été enregistrées à 20 min d’intervalle après l’induction de l’anesthésie. La température du sang a servi de référence. Les températures des quatre autres sites ont été comparées avec celle du sang à l’aide d’analyses de corrélation, de régression et des analyses de Bland et Altman. Nous avons reconnu une exactitude (différence moyenne entre la température de référence et les autres) et une précision (écart type de la différence) de 0,5 °C près comme une différence acceptable en clinique.Résultats: La température «cutanée profonde» était en corrélation avec celle du sang, et avec celle des autres sites, le cofficient de détermination (r2) étant de 0,85 dans chaque cas. Le biais de la température «cutanée profonde» était de 0,0 °C, comme celui de la température tympanique, et plus faible que ceux des températures rectale et œsophagienne. L’écart type de la différence pour la température «cutanée profonde» était de 0,3 °C, comme pour la température rectale.Conclusion: Nous avons démontré que la température frontale pronfonde présentait une grande exactitude et une précision utile suffisante, autant que les trois autres températures centrales, comparée à la température du sang.

Halothane and Enflurane Constrict Canine Mesenteric Arteries by Releasing Ca2+ from Intracellular Ca2+ Stores

Background:Recent studies suggest that volatile anesthetics cause not only vasodilation but also vasoconstriction, depending on the experimental conditions. However, the mechanism of the constrictive effect of volatile anesthetics has not been clarified. The aim of this study was to evaluate the vasoconstrictor effects of halothane, enflurane, and isoflurane and to elucidate the underlying mechanism. Methods:Vascular rings of canine mesenteric arteries were mounted in organ baths, and isometric tension changes were recorded. Changes in intracellular free Ca2+ concentration of vascular smooth muscle were examined by using the fluorescent Ca2+ indicator fura 2 and a dual-wavelength fluorometer. Results:Halothane (0.75–2.3%) and enflurane (1.7–3.4%), but not isoflurane (1.2–3.5%), induced a concentration-dependent transient contraction, followed by a slight, sustained contraction. Halothane (1.5%)- and enflurane (3.4%)-induced contractions were reduced by endothelial denudation and enhanced by indomethacin (10-5 M) treatment but were not affected by L-NG-nitroarginine (10-5 m) or nifedipine (2 X 10-7 M) treatment. Ryanodine (2 X 10-5 M) treatment completely abolished the transient increases in tension and Ca2+ concentration. Even in ryanodine-treated arteries, however, both anesthetics induced a slowly developing sustained contraction, and the sustained contraction induced by enflurane (3.4%) was not accompanied by a significant increase in Ca2+ concentration. Conclusions:Halothane and enflurane, but not isoflurane, induce vasoconstriction by releasing Ca2+ from intracellular stores. Release of a vasodilating prostanoid and endothelium-derived constricting factor may also be involved in the vasoconstrictor effect. Furthermore, increased Ca2+ sensitivity of contractile machinery may be involved in the effect of enflurane.

The bilateral effect of stellate ganglion block on the facial skin blood flow.

Background and Objectives It is our hypothesis that stellate ganglion block increases regional blood flow on the blocked side, but does not change cardiac output, suggesting that the corresponding regional blood flow on the contralateral side may decrease, which would be disadvantageous for patients with bilateral sympatheticallymaintained pain. The aim of this study is to examine the effect of stellate ganglion block on facial skin blood flow. Methods Skin blood flow on the right and left forehead was measured by a laser blood flowmeter before stellate ganglion block and 15 minutes after the block. The block was performed for 8 outpatients with acute or chronic pain in the head or neck using a 24-gauge needle, 5 mL of 1% mepivacaine, and a paratracheal approach at the C6 transverse process. Time control without the block was obtained with 9 healthy volunteers. Results All the patients developed the Horners syndrome on the blocked side, but not on the contralateral side. The facial skin blood flow increased from 7.5 ± 1.1 mL/min/100 g to 14.5 ± 1.4 mL/min/100 g on the blocked side (P < .01) and from 8.8 ± 1.2 mL/min/100 g to 12.8 ± 1.7 mL/min/100 g on the contralateral side (P < .05). The healthy volunteers without the block showed no significant change (from 10.1 ± 0.8 mL/min/100 g to 10.3 ± 0.7 mL/min/100 g). Conclusions Our study suggests that stellate ganglion block may increase the contralateral regional skin blood flow.

Pituitary apoplexy during general anesthesia in beach chair position for shoulder joint arthroplasty.

Pituitary apoplexy is a rare but potentially life-threatening clinical syndrome caused by the sudden enlargement of pituitary adenoma secondary to infarction and/or hemorrhage. It may be the first presentation of previously undiagnosed pituitary adenoma. Although various precipitating factors of pituitary apoplexy are indicated, the pathogenesis remains unknown. In this report, we describe for the first time a case of pituitary apoplexy developed explicitly during general anesthesia supplemented with interscalene brachial plexus block in beach chair or barbershop position for shoulder joint arthroplasty.

The radical scavenger edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) reacts with a pterin derivative and produces a cytotoxic substance that induces intracellular reactive oxygen species generation and cell death.

Cytotoxic effects of the combined use of edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a radical scavenger and an approved medicine for acute brain infarction in Japan, with a pterin derivative, were examined in vitro. When pancreatic cancer cell line Panc-1 cells were incubated with 50 to 400 μM of a pterin derivative, 2-(N,N-dimethylaminomethyleneamino)-6-formyl-3-pivaloylpteridine-4-one (DFP), and the equivalent dose of edaravone, reactive oxygen species (ROS), were generated, and cell death was induced. ROS generation and the loss of mitochondrial membrane potential (MMP) preceding cell death were simultaneously monitored using time-lapse microscopy with an ROS-sensitive dye and a probe to monitor MMP, respectively. Cell death was also estimated quantitatively by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. ROS generation and cell death were prominent when more than 100 μM of each agent was used in combination, whereas the sole use of each agent did not show any effects even at the highest dose, 400 μM. Chemical analysis revealed that DFP and edaravone react immediately in aqueous solution and produce a new compound named DFP-E. DFP-E chemically reacted with NADH much faster than DFP and generated ROS, and biologically, it was much more cell-permeable than DFP. These findings collectively indicated that the combined use of DFP with edaravone produced DFP-E, which caused intracellular ROS generation and cell death. Cell death was observed in normal cells, and edaravone reacted with another pterin derivative to yield an ROS-generating compound. As a result, care should be taken with the clinical use of edaravone when pterin derivatives stay in the body.

Monitored anesthesia care with dexmedetomidine of a patient with severe pulmonary arterial hypertension for inguinal hernioplasty

The presence of severe pulmonary arterial hypertension (PAH) is a significant risk factor of major perioperative cardiovascular complications in patients undergoing even non-cardiac surgery under anesthetic management. The most important aspect of perioperative care of PAH patients is to avoid pulmonary hypertensive crisis, which can be induced by alveolar hypoxia, hypoxemia, hypercarbia, metabolic acidosis, airway manipulations, and activation of the sympathetic nervous system by noxious stimuli. We report a case of successful monitored anesthesia care supplemented by dexmedetomidine for inguinal hernioplasty of a patient with severe PAH secondary to congenital heart disease.

Enhancement of proopiomelanocortin gene promoter activity by local anesthetics in a pituitary cell line.

Background and Objectives: Corticotropin-releasing hormone (CRH) induces gene expression of proopiomelanocortin, a precursor protein of adrenocorticotropic hormone and &bgr;-endorphin, by elevating intracellular cyclic adenosine 3′,5′-monophosphate (cyclic AMP) level in anterior pituitary cells and immune cells. CRH-induced proopiomelanocortin gene expression plays an important role in stress responses and is affected by a variety of drugs, but it is not known whether local anesthetics can directly affect the gene expression. We hypothesized that local anesthetics may directly affect proopiomelanocortin gene expression and can modulate production of adrenocorticotropic hormone and &bgr;-endorphin. Methods: The authors used mouse pituitary tumor cells stably transfected with approximately 0.7 kilobases of the rat proopiomelanocortin 5′ promoter linked with the luciferase gene. In the presence or absence of local anesthetics (lidocaine, mepivacaine, bupivacaine, and ropivacaine), cells were stimulated by CRH or forskolin. After stimulation, proopiomelanocortin gene promoter activity was assessed as luciferase activity, and cyclic AMP efflux was measured by enzymeimmunoassay. Results: CRH- or forskolin-stimulated proopiomelanocortin promoter activity was significantly enhanced by local anesthetics. Cyclic AMP efflux induced by CRH was not significantly increased by local anesthetics. Conclusions: It was concluded that local anesthetics potentiate the effect of CRH or forskolin on proopiomelanocortin promoter activity without changing the intracellular cyclic AMP level. It might be possible that transcriptional regulation mediated by cyclic AMP is also enhanced by local anesthetics in the other cells.