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Background: Anesthetic management of pheochromocytoma and paraganglioma with Fontan circulation is challenging for physicians, with attention to cardiovascular physiology., Case Presentation: We performed anesthetic management for pheochromocytoma and paraganglioma in three patients with Fontan circulation. We maintained intraoperative central venous pressure at preoperative level under fluid infusion and administrating nitric oxide to decrease pulmonary arterial resistance. We administered noradrenaline or vasopressin if low blood pressure was present despite adequate central venous pressure. Although noradrenaline is prevalent for the case of noradrenaline-secreting tumor especially after resection, we could maintain blood pressure to administrate vasopressin without increasing central venous pressure. Retroperitoneal laparoscopic approach which could avoid intra-abdominal adhesions might be selectable as case 3., Conclusions: Sophisticated management is required for pheochromocytoma and paraganglioma with Fontan circulation., (© 2023. The Author(s).)

Background: Hepatectomy for patients with Fontan circulation consists of high central venous pressure and low pulmonary vascular resistance, and is challenging for physicians., Case Presentation: We performed anesthetic management for hepatectomy in three patients with Fontan circulation. Massive bleeding and transfusion as well as careful management were needed. Open abdominal surgery had to be conducted instead of laparoscopic surgery for controlling bleeding in one case. We successfully performed general anesthesia using nitric oxide and inotropes while monitoring arterial pressure and central venous pressure in all the cases., Conclusions: To maintain Fontan circulation during hepatectomy, it is important to manage central venous pressure and ensure appropriate circulatory volume., (© 2022. The Author(s).)

Background: Carbamoyl phosphate synthetase deficiency (CPS1D) is a urea-cycle disorder (UCD). We report successful perioperative management of pediatric living donor liver transplantation (LDLT) in a CPS1D patient., Case Presentation: A 10-year-old female patient with CPS1D underwent LDLT. Proper administration of dextrose 50% and 60 kcal/kg/day with L-arginine and L-carnitine resulted in the avoidance of intraoperative hyperammonemia induced by hypercatabolism. Serum ammonia level transiently increased to 61 mmol/L in the anhepatic phase and decreased to 44 mmol/L after reperfusion., Conclusions: We suggest anesthesia management with administration of dextrose to avoid hyperammonemia during LDLT in patients with CPS1D., (© 2022. The Author(s).)

Background: Postreperfusion syndrome (PRS) after portal vein reperfusion during liver transplantation (LT) has been reported to cause rapid hemodynamic changes and is associated with a prolonged postoperative hospital stay, renal failure, and increased mortality. Although there are some reports on risk factors for PRS in brain-dead donor LT, there are a few reports on those in living donor LT. Therefore, we retrospectively reviewed the factors associated with PRS to contribute to the anesthetic management so as to reduce PRS during living donor LT., Methods: After approval by the ethics committee of our institution, 250 patients aged ≥20 years who underwent living donor LT at our institution between January 2013 and September 2018 were included in the study. A decrease in mean arterial pressure of ≥30% within 5 minutes after portal vein reperfusion was defined as PRS, and estimates and odds ratio (OR) for PRS were calculated using logistic regression. The backward method was used for variable selection in the multivariable analysis., Results: Serum calcium ion concentration before reperfusion (per 0.1 mmol/L increase; OR, 0.74; 95% confidence interval (CI), 0.60-0.95; P < .001), preoperative echocardiographic left ventricular end-diastolic diameter (per 1-mm increase: OR, 0.90; 95% CI, 0.85-0.95; P < .001, men [versus women: OR, 2.45; 95% CI, 1.26-4.75; P = .008]), mean pulmonary artery pressure before reperfusion (restricted cubic spline, P = .003), anhepatic period (restricted cubic spline, P = .02), and graft volume to standard liver volume ratio (restricted cubic spline, P = .03) were significantly associated with PRS., Conclusions: In living donor LT, male sex and presence of small left ventricular end-diastolic diameter, large graft volume, and long anhepatic period are associated with PRS, and a high calcium ion concentration and low pulmonary artery pressure before reperfusion are negatively associated with PRS., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 International Anesthesia Research Society.)

The G protein-gated inwardly rectifying K+ (GIRK) channels play important signaling roles in the central and peripheral nervous systems. However, the role of GIRK channel activation in pain signaling remains unknown mainly due to the lack of potent and selective GIRK channel activators until recently. The present study was designed to determine the effects and mechanisms of ML297, a selective GIRK1/2 activator, on nociception in the spinal cord by using behavioral studies and whole-cell patch-clamp recordings from substantia gelatinosa (SG) neurons. Rats were prepared for chronic lumber catheterization and intrathecal administration of ML297. The nociceptive flexion reflex was tested using an analgesy-meter, and the influence on motor performance was assessed using an accelerating rotarod. We also investigated pre- and post-synaptic actions of ML297 in spinal cord preparations by whole-cell patch-clamp recordings. Intrathecal administration of ML297 increased the mechanical nociceptive threshold without impairing motor function. In voltage-clamp mode of patch-clamp recordings, bath application of ML297 induced outward currents in a dose-dependent manner. The ML297-induced currents demonstrated specific equilibrium potential like other families of potassium channels. At high concentration, ML297 depressed miniature excitatory postsynaptic currents (mEPSCs) but not their amplitude. The ML297-induced outward currents and suppression of mEPSCs were not inhibited by naloxone, a μ-opioid receptor antagonist. These results demonstrated that intrathecal ML297 showed the antinociceptive effect, which was mediated through direct activation of pre- and post-synaptic GIRK channels. Selective GIRK channel activation is a promising strategy for the development of new agents against chronic pain and opioid tolerance., Competing Interests: The authors have declared that no competing interests exist.

Background: Cardiac sarcoidosis (CS) causes severe conduction abnormalities and arrhythmias. CS patients are increasingly being treated with cardiac resynchronization therapy-defibrillators (CRT-Ds). For the first time, we report the anesthetic management of a CS patient with a CRT-D., Case Presentation: A 65-year-old male with an implanted CRT-D due to CS was scheduled for a laparoscopy-assisted total proctocolectomy for his transverse colon cancer. His left ventricular ejection fraction was 32.0%, and his physical status was a New York Heart Association class III. General and epidural anesthesia were performed while using standard monitors and a FloTrac TM system. The dual-chamber pacing (DDD) modality of the CRT-D was unchanged, and its defibrillation function was deactivated before surgery. The surgery was successfully performed, and the patient was discharged without worsening of his cardiac condition., Conclusions: A detailed understanding of this patient's condition, as well as sarcoidosis, helped to facilitate successful anesthetic management of this patient.

Background: Bleeding and carbon dioxide (CO 2 ) gas embolism have been reported as serious complications associated with laparoscopic surgery. We present a case of cerebral infarction presumably caused by CO 2 gas embolism during laparoscopic hepatectomy., Case Presentation: During liver resection, the end-tidal CO 2 suddenly dropped from 40 to 21 mmHg. Simultaneously, ST elevation in lead II and ST depression in lead V5 of the electrocardiogram were observed. After improvement of these electrocardiographic changes, surgery was continued. Postoperatively, incomplete paralysis was present in the right arm and leg. Magnetic resonance imaging revealed cerebral infarction in the broad area of the left cerebral cortex. These complications might have been caused by paradoxical embolism., Conclusion: We should always keep in mind the risk of cerebral infarction with neurological deficits in the case of laparoscopic surgery. Careful monitoring and appropriate treatment for gas embolism are necessary during laparoscopic surgery.

Background: Intestinal pseudo-obstruction, which is a rare complication of pheochromocytoma, can be caused by hypersecreted catecholamines., Case Presentation: A 45-year-old woman was admitted for local recurrence of pheochromocytoma complicated by intestinal pseudo-obstruction. The intestinal pseudo-obstruction showed poor response to α-adrenergic receptor blocker and she was scheduled for surgical resection of pheochromocytoma. The surgery was uneventfully accomplished with general anesthesia combined with epidural anesthesia. The latter was performed with the aim of not only perioperative pain management but also of promoting intestinal peristalsis. The anticipated effect for intestinal peristalsis was not apparent in the early postoperative phase. The abdominal symptoms were gradually relieved over the course of about 1 month., Conclusions: For intestinal pseudo-obstruction induced by pheochromocytoma, although inhibition of the sympathetic system by epidural infusion of local anesthetics may be promising, short-term usage of epidural local anesthetics infusion did not provide a quick recovery after pheochromocytoma removal surgery.

Background: ABO-incompatible living-donor kidney transplantation (LDKT) requires immunotherapy and plasma exchange therapy (PEX). PEX with albumin replacement fluid reportedly decreases fibrinogen levels. However, no reports have described the effects of PEX with albumin replacement fluid on blood coagulation parameters and blood loss during the perioperative period. Therefore, we investigated the effects of preoperative PEX on blood coagulation parameters and blood loss during the perioperative period in patients undergoing ABO-incompatible LDKT as measured by rotational thromboelastometry (ROTEM®)., Methods: Twenty-eight patients undergoing LDKT were divided into the PEX group (ABO incompatible with PEX, n = 13) and non-PEX group (ABO compatible without PEX, n = 15). ROTEM® parameters, standard laboratory test parameters, bleeding volume, and transfusion volume were compared between PEX and non-PEX group. MCE platelet , which represents platelet contribution to clot strength and where "MCE" stands for maximum clot elasticity, was calculated from the difference in MCE between EXTEM and FIBTEM., Results: The bleeding volume during surgery and the intensive care unit (ICU) stay was significantly higher in the PEX than non-PEX group (p < 0.01). Maximum clot firmness (MCF) of EXTEM (MCF EXTEM ), MCF FIBTEM , and MCE platelet was significantly lower in the PEX than non-PEX group (p < 0.01). In the PEX group, the bleeding volume during surgery was very strongly correlated with the baseline MCF EXTEM and MCE platelet , and the bleeding volume during the ICU stay was strongly correlated with the postoperative MCF EXTEM and MCE platelet ., Conclusions: These results suggest that the increased blood loss in the PEX group during surgery and the ICU stay was associated with decreased platelet contribution to clot strength as measured by ROTEM®., Trial Registration: UMIN-Clinical Trial Registry UMIN000018355 . Registered 21 July 2015.

Background: Ultiva® is commonly administered intravenously for analgesia during general anaesthesia and its main constituent remifentanil is an ultra-short-acting μ-opioid receptor agonist. Ultiva® is not approved for epidural or intrathecal use in clinical practice. Previous studies have reported that Ultiva® provokes opioid-induced hyperalgesia by interacting with spinal dorsal horn neurons. Ultiva® contains glycine, an inhibitory neurotransmitter but also an N-methyl-D-aspartate receptor co-activator. The presence of glycine in the formulation of Ultiva® potentially complicates its effects. We examined how Ultiva® directly affects nociceptive transmission in the spinal cord., Methods: We made patch-clamp recordings from substantia gelatinosa (SG) neurons in the adult rat spinal dorsal horn in vivo and in spinal cord slices. We perfused Ultiva® onto the SG neurons and analysed its effects on the membrane potentials and synaptic responses activated by noxious mechanical stimuli., Results: Bath application of Ultiva® hyperpolarized membrane potentials under current-clamp conditions and produced an outward current under voltage-clamp conditions. A barrage of excitatory postsynaptic currents (EPSCs) evoked by the stimuli was suppressed by Ultiva®. Miniature EPSCs (mEPSCs) were depressed in frequency but not amplitude. Ultiva®-induced outward currents and suppression of mEPSCs were not inhibited by the μ-opioid receptor antagonist naloxone, but were inhibited by the glycine receptor antagonist strychnine. The Ultiva®-induced currents demonstrated a specific equilibrium potential similar to glycine., Conclusions: We found that intrathecal administration of Ultiva® to SG neurons hyperpolarized membrane potentials and depressed presynaptic glutamate release predominantly through the activation of glycine receptors. No Ultiva®-induced excitatory effects were observed in SG neurons. Our results suggest different analgesic mechanisms of Ultiva® between intrathecal and intravenous administrations.

Mutant mouse models are indispensable tools for clarifying the functions of genes and elucidating the underlying pathogenic mechanisms of human diseases. We carried out large-scale mutagenesis using the chemical mutagen N-ethyl-N-nitrosourea. One specific aim of our mutagenesis project was to generate novel cancer models. We screened 7012 animals for dominant traits using a necropsy test and thereby established 17 mutant lines predisposed to cancer. Here, we report on a novel cancer model line that developed osteoma, trichogenic tumor, and breast cancer. Using fine mapping and genomic sequencing, we identified a point mutation in the adenomatous polyposis coli (Apc) gene. The Apc1576 mutants bear a nonsense mutation at codon 1576 in the Apc gene. Although most Apc mutant mice established thus far have multifocal intestinal tumors, mice that are heterozygous for the Apc1576 mutation do not develop intestinal tumors; instead, they develop multifocal breast cancers and trichogenic tumors. Notably, the osteomas that develop in the Apc1576 mutant mice recapitulate the lesion observed in Gardner syndrome, a clinical variant of familial adenomatous polyposis. Our Apc1576 mutant mice will be valuable not only for understanding the function of the Apc gene in detail but also as models of human Gardner syndrome., (© 2013 Japanese Cancer Association.)

The Ca(2+)-permeable cation channel TRPA1 acts as an ionotropic receptor for various pungent compounds and as a noxious cold sensor in sensory neurons. It is unclear what proportion of the TRPA1-mediated current is carried by Ca(2+) ions and how the permeation pathway changes during stimulation. Here, based on the relative permeability of the nonstimulated channel to cations of different size, we estimated a pore diameter of approximately 11 A. Combined patch-clamp and Fura-2 fluorescence recordings revealed that with 2 mM extracellular Ca(2+), and at a membrane potential of -80 mV, approximately 17% of the inward TRPA1 current is carried by Ca(2+). Stimulation with mustard oil evoked an apparent dilatation of the pore of 3 A and an increase in divalent cation selectivity and fractional Ca(2+) current. Mutations in the putative pore that reduced the divalent permeability and fractional Ca(2+) current also prevented mustard-oil-induced increases in Ca(2+) permeation. It is interesting that fractional Ca(2+) currents for wild-type and mutant TRPA1 were consistently higher than values predicted based on biionic reversal potentials using the Goldman-Hodgkin-Katz equation, suggesting that binding of Ca(2+) in the pore hinders monovalent cation permeation. We conclude that the pore of TRPA1 is dynamic and supports a surprisingly large Ca(2+) influx., (2010 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

TRPA1 functions as an excitatory ionotropic receptor in sensory neurons. It was originally described as a noxious cold-activated channel, but its cold sensitivity has been disputed in later studies, and the contribution of TRPA1 to thermosensing is currently a matter of strong debate. Here, we provide several lines of evidence to establish that TRPA1 acts as a cold sensor in vitro and in vivo. First, we demonstrate that heterologously expressed TRPA1 is activated by cold in a Ca(2+)-independent and Ca(2+) store-independent manner; temperature-dependent gating of TRPA1 is mechanistically analogous to that of other temperature-sensitive TRP channels, and it is preserved after treatment with the TRPA1 agonist mustard oil. Second, we identify and characterize a specific subset of cold-sensitive trigeminal ganglion neurons that is absent in TRPA1-deficient mice. Finally, cold plate and tail-flick experiments reveal TRPA1-dependent, cold-induced nociceptive behavior in mice. We conclude that TRPA1 acts as a major sensor for noxious cold.

Calcium signaling controls multiple cellular functions and is regulated by the release from internal stores and entry from extracellular fluid. In bone, osteoclast differentiation is induced by RANKL (receptor activator of NF-kappaB ligand)-evoked intracellular Ca(2+) oscillations, which trigger nuclear factor-activated T cells (NFAT) c1-responsive gene transcription. However, the Ca(2+) channels involved remain largely unidentified. Here we show that genetic ablation in mice of Trpv4, a Ca(2+)-permeable channel of the transient receptor potential (TRP) family, increases bone mass by impairing bone resorption. TRPV4 mediates basolateral Ca(2+) influx specifically in large osteoclasts when Ca(2+) oscillations decline. TRPV4-mediated Ca(2+) influx hereby secures intracellular Ca(2+) concentrations, ensures NFATc1-regulated gene transcription, and regulates the terminal differentiation and activity of osteoclasts. In conclusion, our data indicate that Ca(2+) oscillations and TRPV4-mediated Ca(2+) influx are sequentially required to sustain NFATc1-dependent gene expression throughout osteoclast differentiation, and we propose TRPV4 as a therapeutic target for bone diseases.

Clotrimazole (CLT) is a widely used drug for the topical treatment of yeast infections of skin, vagina, and mouth. Common side effects of topical CLT application include irritation and burning pain of the skin and mucous membranes. Here, we provide evidence that transient receptor potential (TRP) channels in primary sensory neurons underlie these unwanted effects of CLT. We found that clinically relevant CLT concentrations activate heterologously expressed TRPV1 and TRPA1, two TRP channels that act as receptors of irritant chemical and/or thermal stimuli in nociceptive neurons. In line herewith, CLT stimulated a subset of capsaicin-sensitive and mustard oil-sensitive trigeminal neurons, and evoked nocifensive behavior and thermal hypersensitivity with intraplantar injection in mice. Notably, CLT-induced pain behavior was suppressed by the TRPV1-antagonist BCTC [(N-(-4-tertiarybutylphenyl)-4-(3-cholorpyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamide)] and absent in TRPV1-deficient mice. In addition, CLT inhibited the cold and menthol receptor TRPM8, and blocked menthol-induced responses in capsaicin- and mustard oil-insensitive trigeminal neurons. The concentration for 50% inhibition (IC50) of inward TRPM8 current was approximately 200 nM, making CLT the most potent known TRPM8 antagonist and a useful tool to discriminate between TRPM8- and TRPA1-mediated responses. Together, our results identify TRP channels in sensory neurons as molecular targets of CLT, and offer means to develop novel CLT preparations with fewer unwanted sensory side effects.

TRPA1 is a calcium-permeable nonselective cation transient receptor potential (TRP) channel that functions as an excitatory ionotropic receptor in nociceptive neurons. TRPA1 is robustly activated by pungent substances in mustard oil, cinnamon, and garlic and mediates the inflammatory actions of environmental irritants and proalgesic agents. Here, we demonstrate a bimodal sensitivity of TRPA1 to menthol, a widely used cooling agent and known activator of the related cold receptor TRPM8. In whole-cell and single-channel recordings of heterologously expressed TRPA1, submicromolar to low-micromolar concentrations of menthol cause channel activation, whereas higher concentrations lead to a reversible channel block. In addition, we provide evidence for TRPA1-mediated menthol responses in mustard oil-sensitive trigeminal ganglion neurons. Our data indicate that TRPA1 is a highly sensitive menthol receptor that very likely contributes to the diverse psychophysical sensations after topical application of menthol to the skin or mucous membranes of the oral and nasal cavities.

We have investigated the cellular mechanisms of mechanical stress-induced immediate responses in human umbilical vein endothelial cells (HUVECs). Hypotonic stress (HTS) induced ATP release, which evoked a Ca(2+) transient, followed by actin reorganization within a few minutes, in HUVECs. Disruption of the actin cytoskeleton did not suppress HTS-induced ATP release, and inhibition of the ATP-mediated Ca(2+) response did not affect actin reorganization, thereby indicating that these two responses are not interrelated. ATP release and actin reorganization were also induced by lysophosphatidic acid (LPA). HTS and LPA induced membrane translocation of RhoA, which occurs when RhoA is activated, and tyrosine phosphorylation of focal adhesion kinase (FAK) and paxillin. Tyrosine kinase inhibitors (herbimycin A or tyrphostin 46) inhibited both HTS- and LPA-induced ATP release and actin reorganization, but did not affect RhoA activation. In contrast, Rho-kinase inhibitor (Y27632) inhibited all of the HTS- and LPA-induced responses. These results indicate that the activation of the RhoA/Rho-kinase pathway followed by tyrosine phosphorylation of FAK and paxillin leads to ATP release and actin reorganization in HUVECs. Furthermore, the fact that HTS and LPA evoke exactly the same intracellular signals and responses suggests that even these immediate mechanosensitive responses are in fact not mechanical stress-specific.

Surgical operations often induce acute hyperglycemia, which is known to affect endothelial functions. In this study, we examined the effects of propofol, a commonly used general anaesthetic, on bovine aortic endothelial cell (BAEC) dysfunction induced by glucose overload. 2 D-glucose overload (23 mM) induced an accumulation of superoxide anion (O2-), assessed by MCLA chemiluminescence, to a similar extent as that generated by 233 microU ml(-1) xanthine oxidase (XO) and 100 micro M xanthine. Propofol inhibited this accumulation with an IC50 of 0.21 micro M, whereas much higher concentrations of propofol were required to scavenge O2- generated by 250 microU ml(-1) XO and 100 microM xanthine (IC50: 13.5 micro M). 3 D-glucose overload attenuated ATP-induced NO production which was detected using diaminofluorescence-2 (DAF-2). The inhibition was reversed by propofol with an EC50 of 0.60 microM. In contrast, inhibitions caused by xanthine/XO were not altered by propofol (1 microM). 4 D-glucose overload suppressed ATP-induced Ca2+ oscillations and capacitative Ca2+ entry (CCE), which were both restored by superoxide dismutase, indicating that O2- was responsible. Propofol restored these attenuated Ca2+ oscillations and CCE with EC50 of 0.31 and 1.0 microM, respectively. 5 D-glucose overload (23 mM) increased the intracellular glucose concentration 4 fold, compared with cells exposed to 5.75 mM glucose, and 1 micro M propofol reduced this increase to 2.8 fold. 6 We conclude from these results that anaesthetic concentrations of propofol prevent the impairment of Ca2+-dependent NO production in BAEC induced by glucose overload. This effect is mainly due to the reduction of O2- accumulation, and involves, at least in part, the inhibition of cellular glucose uptake.

We examined the effects of superoxide anion (O) generated by xanthine plus xanthine oxidase (X/XO) on the intracellular Ca(2+) concentration ([Ca(2+)](i)) and muscle contractility in cultured bovine aortic smooth muscle cells (BASMC). Cells were grown on collagen-coated dish for the measurement of [Ca(2+)](i). Pretreatment with X/XO inhibited ATP-induced Ca(2+) transient and Ca(2+) release-activated Ca(2+) entry (CRAC) after thapsigargin-induced store depletion, both of which were reversed by superoxide dismutase (SOD). In contrast, Ca(2+) transients induced by high-K(+) solution and Ca(2+) ionophore A-23187 were not affected by X/XO. BASMC-embedded collagen gel lattice, which was pretreated with xanthine alone, showed contraction in response to ATP, thapsigargin, high-K(+) solution, and A-23187. Pretreatment of the gel with X/XO impaired gel contraction not only by ATP and thapsigargin, but also by high-K(+) solution and A-23187. The X/XO-treated gel showed normal contraction; however, when SOD was present during the pretreatment period. These results indicate that O(2)(-) attenuates smooth muscle contraction by impairing CRAC, ATP-induced Ca(2+) transient, and Ca(2+) sensitivity in BASMC.