Intraoperative Transesophageal Echocardiography Evaluation of Tricuspid Valve Re-repair for Ebstein's Anomaly.

Postoperative stenosis or regurgitation of the tricuspid valve is common and affects the prognosis after repair surgery of Ebstein's anomaly. However, it is unclear how intraoperative echocardiography influences the postoperative course. We report a longitudinal echocardiography course including intraoperative transesophageal echocardiography in a cone reconstruction procedure for Ebstein's anomaly in a 17-year-old woman. Tight tricuspid valvuloplasty was preferred, but the tricuspid annulus enlarged rather after surgery. The evaluation of the tricuspid valve form and function using intraoperative echocardiography could support the surgeon's impression.

Association between intraoperative pulmonary artery pressure and cardiovascular complications after off-pump coronary artery bypass surgery: a single-center observational study.

BACKGROUND: The impact of intraoperative pulmonary hemodynamics on prognosis after off-pump coronary artery bypass (OPCAB) surgery remains unknown. In this study, we examined the association between intraoperative vital signs and the development of major adverse cardiovascular events (MACE) during hospitalization or within 30 days postoperatively. METHODS: This retrospective study analyzed data from a university hospital. The study cohort comprised consecutive patients who underwent isolated OPCAB surgery between November 2013 and July 2021. We calculated the mean and coefficient of variation of vital signs obtained from the intra-arterial catheter, pulmonary artery catheter, and pulse oximeter. The optimal cut-off was defined as the receiver operating characteristic curve (ROC) with the largest Youden index (Youden index = sensitivity + specificity - 1). Multivariate logistic regression analysis ROC curves were used to adjust all baseline characteristics that yielded P values of < 0.05. RESULTS: In total, 508 patients who underwent OPCAB surgery were analyzed. The mean patient age was 70.0 ± 9.7 years, and 399 (79%) were male. There were no patients with confirmed or suspected preoperative pulmonary hypertension. Postoperative MACE occurred in 32 patients (heart failure in 16, ischemic stroke in 16). The mean pulmonary artery pressure (PAP) was significantly higher in patients with than without MACE (19.3 ± 3.0 vs. 16.7 ± 3.4 mmHg, respectively; absolute difference, 2.6 mmHg; 95% confidence interval, 1.5 to 3.8). The area under the ROC curve of PAP for the prediction of MACE was 0.726 (95% confidence interval, 0.645 to 0.808). The optimal mean PAP cut-off was 18.8 mmHg, with a specificity of 75.8% and sensitivity of 62.5% for predicting MACE. After multivariate adjustments, high PAP remained an independent risk factor for MACE. CONCLUSIONS: Our findings provide the first evidence that intraoperative borderline pulmonary hypertension may affect the prognosis of patients undergoing OPCAB surgery. Future large-scale prospective studies are needed to verify the present findings.

Warfarin Reversal With Four-Factor Prothrombin Complex Concentrate for Left Ventricular Assist Device Conversion Surgery Monitored by TEG6s: A Case Report.

Left ventricular assist devices (LVADs) require careful therapeutic anticoagulation with warfarin to prevent pump thrombosis. However, the best method to reverse warfarin for elective LVAD conversion surgery with massive bleeding remains unclear. We report the case of a 39-year-old Japanese man who was administered a four-factor prothrombin complex concentrate (4F-PCC) as warfarin reversal when he underwent conversion surgery from paracorporeal LVAD to implantable LVAD. 4F-PCC with co-administration of vitamin K reduced the international normalized ratio and R time in TEG6s (Haemonetics Corporation, USA) immediately. The effect was prolonged, and good hemostasis was achieved. 4F-PCC with vitamin K provided good hemostasis in our patient; therefore, 4F-PCC could be a useful tool for elective LVAD conversion surgery with expected massive bleeding and requiring immediate warfarin reversal.

The Value of Routine Tests before Pediatric Eye Surgery: A 10-Year Experience at a Tertiary Care Hospital.

Background: Routine tests before ophthalmologic surgery in adult patients are no longer recommended. However, there are limited data on the utility of routine preoperative tests for children. Aims: We aimed to describe the effect of routine preoperative tests on systemic perioperative complications by hospital discharge or by day 30 following eye surgery. Settings and Design: This was a single-center, observational, and descriptive study. Subjects and Methods: We examined all patients ≤ 17 years old for whom ophthalmologists consulted with anesthesiologists before eye surgery under general anesthesia in an academic teaching tertiary care hospital from January 2010 to December 2019. Results: A total of 708 pediatric patients were analyzed. The mean patient age was 8.5 ± 4.6 years. The most frequently performed procedure was strabismus surgery in 433 patients (61.2%). Following anesthetic consultations, 15 patients (2.1%) underwent surgery postponed due to abnormalities at the physical examination. Routine tests identified that the two patients (0.3%) required additional evaluations due to elevated serum creatine kinase and electrocardiographic abnormalities. However, further examinations found that these abnormalities were unremarkable. The remaining 691 patients (97.6%) underwent surgery as scheduled. Substantial intraoperative blood loss was observed only in three patients with malignant tumors or trauma. The incidence of systemic complications was 0 (0%; 95% confidence interval, 0%-0.05%). Conclusions: These data indicated that the development of systemic perioperative complications following pediatric ophthalmic surgery is rare. Preoperative tests should be requested only if they are clinically indicated or before potentially bleeding procedures, such as malignancy or trauma surgery.

Anaesthetic management using remimazolam in a patient with severe aortic stenosis: a case report.

BACKGROUND: The administration of general anaesthesia in patients with aortic stenosis (AS) requires careful attention to haemodynamics. We used remimazolam for the induction and maintenance of anaesthesia in a woman with severe AS undergoing a total mastectomy. CASE PRESENTATION: An 81-year-old woman with severe AS was scheduled to undergo a total mastectomy. We decided to administer total intravenous anaesthesia with remimazolam to minimize haemodynamic changes. Although the patient showed transient hypotension after anaesthesia induction, the cardiac index was preserved with a low dose of continuous noradrenaline. The anaesthesia was then safely maintained without a decrease in the patient's cardiac index. CONCLUSIONS: General anaesthesia using remimazolam preserved cardiac output in this patient; therefore, remimazolam can be safely used to avoid the risk of cardiac suppression in patients with severe AS.

Limited Utility of Routine Tests Prior to Ophthalmologic Surgery: An Observational Study in a Japanese Hospital.

INTRODUCTION: Routine preoperative testing for low-risk surgeries without a clinical indication should be avoided; however, such tests are still frequently performed in Japan. This study was performed to assess the impact of routine preoperative tests in low-risk surgery in a Japanese medical setting. METHODS: We performed a retrospective chart review to examine the utility of routine tests with respect to anesthetic management and postoperative complications in all patients aged ≥ 18 years whom ophthalmologists consulted with anesthesiologists before ophthalmologic surgery under general anesthesia. RESULTS: During the 10-year study period, 1,234 anesthetic consultations and 1,211 routine preoperative tests (laboratory tests, chest X-rays, and electrocardiograms) were performed in Toyama University Hospital. In total, 59 patients (4.8% of the study population) canceled surgery after a battery of preoperative evaluation. Among them, 10 patients had incidental abnormalities that necessitated additional tests, and only three patients (0.2%) canceled surgery. In-hospital postoperative complications developed in nine patients (0.7%) whose routine test results made it difficult to predict development of these adverse events. No severe life-threatening events were noted in this survey. CONCLUSIONS: Routine tests prior to eye surgery for adults were of low value for perioperative management and prediction of development of in-hospital complications in this Japanese medical setting. Anesthesiologists and ophthalmologists should selectively order preoperative tests based on the medical interview and physical examination.

Role of G protein-coupled receptor kinase 2 in oxidative and nitrosative stress-related neurohistopathological changes in a mouse model of sepsis-associated encephalopathy.

Sepsis-associated encephalopathy (SAE), characterized as diffuse brain dysfunction and neurological manifestations secondary to sepsis, is a common complication in critically ill patients and can give rise to poor outcome, but understanding the molecular basis of this disorder remains a major challenge. Given the emerging role of G protein-coupled receptor 2 (GRK2), first identified as a G protein-coupled receptor (GPCR) regulator, in the regulation of non-G protein-coupled receptor-related molecules contributing to diverse cellular functions and pathology, including inflammation, we tested the hypothesis that GRK2 may be linked to the neuropathogenesis of SAE. When mouse MG6 microglial cells were challenged with lipopolysaccharide (LPS), GRK2 cytosolic expression was highly up-regulated. The ablation of GRK2 by small interfering RNAs (siRNAs) prevented an increase in intracellular reactive oxygen species generation in LPS-stimulated MG6 cells. Furthermore, the LPS-induced up-regulation of inducible nitric-oxide synthase expression and increase in nitric oxide production were negated by GRK2 inhibitor or siRNAs. However, GRK2 inhibition was without effect on overproduction of tumor necrosis factor-α, interleukin (IL)-6, and IL-1ß in LPS-stimulated MG cells. In mice with cecal ligation and puncture-induced sepsis, treatment with GRK2 inhibitor reduced high levels of oxidative and nitrosative stress in the mice brains, where GRK2 expression was up-regulated, alleviated neurohistological damage observed in cerebral cortex sections, and conferred a significant survival advantage to CLP mice. Altogether, these results uncover the novel role for GRK2 in regulating cellular oxidative and nitrosative stress during inflammation and suggest that GRK2 may have a potential as an intriguing therapeutic target to prevent or treat SAE.

Prevalence of chronic postsurgical pain after thoracotomy and total knee arthroplasty: a retrospective multicenter study in Japan (Japanese Study Group of Subacute Postoperative Pain).

We performed a multicenter observational study to assess the prevalence and risk factors of persistent pain after lung cancer surgery and total knee arthroplasty (TKA) in the Japanese population. After receiving Ethics Committee approval, a retrospective chart review was performed for patients who underwent surgery at seven university hospitals in Japan in 2013. A total of 511 patients who underwent lung cancer surgery and 298 patients who underwent TKA were included. The prevalence of chronic postsurgical pain (CPSP) at 3 and 6 months was 18 and 12% after lung surgery and 49 and 33% after TKA, respectively. The prevalence of analgesic use at 3 and 6 months was 16 and 9% after lung surgery and 34 and 22% after TKA, respectively. In both groups, preoperative analgesic use was associated with CPSP. Anesthetic methods or techniques during both types of surgery did not significantly affect the prevalence of CPSP. This is the first study in which the prevalence of CPSP after lung surgery and TKA in Japanese population was extensively evaluated in a multicenter trial. Further prospective studies are needed to confirm the prevalence of CPSP in the Japanese population and to identify risk factors and prevention methods.

A selective inhibition of c-Fos/activator protein-1 as a potential therapeutic target for intervertebral disc degeneration and associated pain.

Intervertebral disc (IVD) degeneration is a major cause of low back pain. The transcription factor c-Fos/Activator Protein-1 (AP-1) controls the expression of inflammatory cytokines and matrix metalloproteinases (MMPs) that contribute to the pathogenesis IVD degeneration. We investigated the effects of inhibition of c-Fos/AP-1 on IVD degeneration and associated pain. A selective inhibitor, T-5224, significantly suppressed the interleukin-1ß-induced up-regulation of Mmp-3, Mmp-13 and Adamts-5 transcription in human nucleus pulposus cells and in a mouse explant culture model of IVD degeneration. We used a tail disc percutaneous needle puncture method to further assess the effects of oral administration of T-5224 on IVD degeneration. Analysis of disc height, T2-magnetic resonance imaging (MRI) findings, and histology revealed that IVD degeneration was significantly mitigated by T-5224. Further, oral administration of T-5224 ameliorated pain as indicated by the extended tail-flick latency in response to heat stimulation of rats with needle-puncture-induced IVD degeneration. These findings suggest that the inhibition of c-Fos/AP-1 prevents disc degeneration and its associated pain and that T-5224 may serve as a drug for the prevention of IVD degeneration.

Usefulness for the combination of G-protein- and ß-arrestin-biased ligands of µ-opioid receptors: Prevention of antinociceptive tolerance.

Background: µ-Opioid receptor internalization is considered to be critically linked to antinociceptive tolerance. Although µ-opioid receptor agonists have been administered simultaneously with other drugs to control pain, little information is available regarding opioid­opioid interactions. Therefore, the present study was designed to further investigate the utility of a new G protein-biased ligand for µ-opioid receptors, TRV130, which has an antinociceptive effect without ß-arrestin-dependent µ-opioid receptor internalization, and its combination with fentanyl using µ-opioid receptor-expressing cells and mice. Results: In the present study, we confirmed that fentanyl produced a profound increase in ß-arrestin-2 recruitment accompanied by µ-opioid receptor internalization, whereas TRV130 did not induce either the recruitment of ß-arrestin-2 or µ-opioid receptor internalization in µ-opioid receptor-expressing cells. Under these conditions, ß-arrestin-2 recruitment accompanied by µ-opioid receptor internalization induced by fentanyl was abolished by TRV130, whereas TRV130 did not alter the reduction of cyclic adenosine monophosphate formation by fentanyl in µ-opioid receptor-expressing cells. In a behavioral assay, TRV130 exerted an antinociceptive effect in a hot-plate test in mice. In a combination test, the antinociceptive effect of TRV130 was synergistically increased by fentanyl. Fentanyl induced antihyperalgesia and development of its tolerance under a neuropathic pain-like state following sciatic nerve ligation. However, treatment of mice with an antinociceptive dose of TRV130 did not induce the rapid development of tolerance to its antihyperalgesic effect under a neuropathic pain-like state. Furthermore, the rapid development of tolerance to the antihyperalgesic effect induced by fentanyl plus TRV130 in mice with sciatic nerve ligation was not observed, unlike in the case of fentanyl alone. Conclusions: These findings provide evidence that activation of the G protein-biased pathway through µ-opioid receptors can alter signaling in the ß-arrestin-2 pathway linked to the stimulation of µ-opioid receptors. Furthermore, the combination of G protein-biased and ß-arrestin-biased ligands of µ-opioid receptors exerts an ideal antinociceptive effect without the rapid development of antinociceptive tolerance.

Increased risk of paclitaxel-induced peripheral neuropathy in patients using clopidogrel: a retrospective pilot study.

Paclitaxel-induced peripheral neuropathy (PIPN) is one of the serious adverse events associated with paclitaxel-based cancer treatments. A recent case study showed that the antiplatelet agent clopidogrel inhibits paclitaxel metabolism via cytochrome P450 (CYP) 2C8, resulting in severe PIPN. The aim of this study was to determine the impact of clopidogrel as a risk factor for the development of PIPN, using a retrospective cohort study. Data from paclitaxel-treated patients with or without clopidogrel and low-dose aspirin treatment were retrieved from medical charts. A total of 161 adult patients were included in this study: 135 were controls, 9 were clopidogrel-treated and 17 were aspirin-treated. The clopidogrel group had a greater proportion of males and a higher rate of comorbidities, such as diabetes mellitus and dyslipidemia, than the control group. However, patient characteristics were similar between the clopidogrel and aspirin groups. Severe PIPN was diagnosed in 3 (2.2%) and 2 (22.2%) patients in the control and clopidogrel groups, respectively (odds ratio: 12.0; p = 0.031). No patients in the aspirin group presented with severe neuropathy. These pilot data suggest that concomitant treatment with clopidogrel leads to a greater risk of PIPN. The avoidance of concomitant clopidogrel use may be effective in reducing clopidogrel-associated PIPN.

[Retrospective Analysis of Postoperative Acute Kidney Injury in Patients Undergoing Off-pump Coronary Artery Bypass Surgery].

BACKGROUND: Recent study has shown that postoperative acute kidney injury (AKI) increases postoperative mortality and complications, but correlation between perioperative factors in cardiac surgery and AKI still remains to be explored. The present retrospective study was performed to evaluate the predictors of postoperative AKI in patients undergoing off-pump coronary artery bypass surgery (OPCAB). METHODS: We studied 233 patients undergoing OPCAB at Toyama University Hospital between January 2009 and March 2013. Logistic regression analyses were used to determine whether perioperative factors were associated with postoperative AKI. RESULTS: Postoperative AKI occurred in 39% of the patients. There were statistically significant associations between postoperative AKI and perioperative factors including BMI (multivariable odds ratio, 1.83; 95% Ci, 1.14 to 3.88), hypertension (multivariable odds ratio, 1.80; 95% CI, 1.01 to 3.23), intraoperative urine output (multivariable odds ratio, 1.85; 95% CI, 1.02 to 3.39) and postoperative anemia (multivariable odds ratio, 2.24; 95% CI, 1.24 to 4.12). CONCLUSIONS: In this study, we found that preoperative BMI, hypertension, intraoperative urine output and postoperative anemia might be predictors of postoperative AKI in OPCAB surgery patients.

Changes in the expression of IL-6-Mediated MicroRNAs in the dorsal root ganglion under neuropathic pain in mice.

A multiplex analysis for profiling the expression of candidate microRNAs (miRNAs), which are small noncoding RNAs that function as key post-transcriptional regulators, may lead to a better understanding of the complex machinery of neuropathic pain. In the present study, we performed a miRNA array analysis using tissues of the dorsal root ganglion (DRG), a primary site for pain processing, obtained from mice with partial sciatic nerve ligation. Among 1135 total miRNAs, 26 miRNAs showed up-regulation (more than 2-fold change) and only 4 miRNAs showed down-regulation (less than 0.5-fold change) in the DRG of nerve-ligated mice. In a RT-qPCR assay, the levels of miR-21, miR-431, and miR-511-3p were significantly increased on the ipsilateral side of the DRG from 3 to 7 days after sciatic nerve ligation. These elevations were almost absent in IL-6 knockout mice. Furthermore, the expression level of miR-21, but not those of miR-431 or miR511-3p, was significantly increased in exosomes extracted from blood of nerve-ligated mice. These findings suggest that the increased expression of IL-6-regulated miR-21, miR-431, and miR-511-3p in the DRG and increased exosomal miR-21 extracted from blood after sciatic nerve ligation may play at least a partial role in neuropathic pain. Synapse 70:317-324, 2016. © 2016 Wiley Periodicals, Inc.

Cerebral oxygenation in the beach chair position before and during general anesthesia in patients with and without cardiovascular risk factors.

STUDY OBJECTIVES: To evaluate changes in cerebral tissue oxygen index (TOI) values under the beach chair position before and during general anesthesia in surgical patients with or without cardiovascular risk factors. DESIGN: Prospective study. SETTING: Operating room in the university hospital. PATIENTS: Ninety-one patients undergoing surgery, including healthy patients (n = 28), patients with 1 cardiovascular risk factor (n = 33), and those with more than 1 risk factor (n = 30). INTERVENTIONS AND MEASUREMENTS: Cerebral TOI the day before and during general anesthesia was evaluated using a near-infrared spectroscopy NIRO-200 (Hamamatsu Photonics, Hamamatsu, Japan) for each patient. The initial TOI measurement in the supine position after a 10-minute rest or 10 minute after the endotracheal intubation was followed by measurements in 30° and subsequent 60° upright position for 5 minutes. Phenylephrine 0.1 mg and/or ephedrine 4 mg was administered intravenously to maintain mean blood pressure above 60 mm Hg accordingly. MAIN RESULTS: The beach chair position decreased mean arterial blood pressure and heart rate under general anesthesia, although patients with more than 1 cardiovascular risk factor needed significantly more phenylephrine doses to maintain mean blood pressure above 60 mm Hg. Values of TOI were within the normal range of about 70% before and during anesthesia in all groups. CONCLUSIONS: The beach chair position under general anesthesia did not alter cerebral oxygenation in patients with or without cardiovascular risk factors showing normal preoperative cerebral TOI values when the mean blood pressure was maintained above 60 mm Hg. The careful management using the cerebral oxygenation monitoring appears to maintain cerebral perfusion in the beach chair position during general anesthesia.

Mechanisms of cisplatin-induced muscle atrophy.

Fatigue is the most common side effect of chemotherapy. However, the mechanisms of "muscle fatigue" induced by anti-cancer drugs are not fully understood. We therefore investigated the muscle-atrophic effect of cisplatin, a platinum-based anti-cancer drug, in mice. C57BL/6J mice were treated with cisplatin (3mg/kg, i.p.) or saline for 4 consecutive days. On Day 5, hindlimb and quadriceps muscles were isolated from mice. The loss of body weight and food intake under the administration of cisplatin was the same as those in a dietary restriction (DR) group. Under the present conditions, the administration of cisplatin significantly decreased not only the muscle mass of the hindlimb and quadriceps but also the myofiber diameter, compared to those in the DR group. The mRNA expression levels of muscle atrophy F-box (MAFbx), muscle RING finger-1 (MuRF1) and forkhead box O3 (FOXO3) were significantly and further increased by cisplatin treated group, compared to DR. Furthermore, the mRNA levels of myostatin and p21 were significantly upregulated by the administration of cisplatin, compared to DR. On the other hand, the phosphorylation of Akt and FOXO3a, which leads to the blockade of the upregulation of MuRF1 and MAFbx, was significantly and dramatically decreased by cisplatin. These findings suggest that the administration of cisplatin increases atrophic gene expression, and may lead to an imbalance between protein synthesis and protein degradation pathways, which would lead to muscle atrophy. This phenomenon could, at least in part, explain the mechanism of cisplatin-induced muscle fatigue.

Inhibition of histone deacetylases protects septic mice from lung and splenic apoptosis.

BACKGROUND: Epigenetic programming, dynamically regulated by histone acetylation, may play a key role in the pathophysiology of sepsis. We examined whether histone deacetylase (HDAC) can contribute to sepsis-associated inflammation and apoptosis. MATERIALS AND METHODS: Polymicrobial sepsis was induced by cecal ligation and puncture (CLP) in BALB/c mice. An intraperitoneal injection of CG200745 (10 mg/kg), a novel broad-spectrum HDAC inhibitor, or valproic acid (500 mg/kg), a predominant inhibitor of class I HDACs, was given 3 h before surgery. RESULTS: HDAC1, HDAC2, and HDAC3 protein levels were decreased in lungs after CLP. Furthermore, CLP-induced sepsis increased both histone H3 and H4 acetylation levels in lungs. When CG200745 was given, apoptosis induction was strongly suppressed in lungs and spleens of septic mice. This antiapoptotic effect of CG200745 was not accompanied by upregulation of antiapoptotic and downregulation of proapoptotic Bcl-2 family member proteins. Treatment with CG200745 failed to inhibit elevated levels of serum cytokines and prevent lung inflammation in septic mice. Valproic acid also showed antiapoptotic but not anti-inflammatory effects in septic mice. CONCLUSIONS: These findings imply that HDAC inhibitors are a unique agent to prevent cell apoptosis in sepsis at their doses that do not improve inflammatory features, indicating that septic inflammation and apoptosis may not necessarily be essential for one another's existence. This study also represents the first report that CLP-induced sepsis downregulates HDACs. Nevertheless, the data with HDAC inhibitors suggest that imbalance in histone acetylation may play a contributory role in expression or repression of genes involved in septic cell apoptosis.

[A case of upper airway obstruction associated with flexed cervical position after posterior occipito-cervical fusion--a retrospective radiographic analysis by the O-C2 angle].

A 71-year-old female developed upper airway obstruction due to flexed cervical position after posterior occipito-cervical fusion. After the operation, she was re-intubated with the air-Q intubating laryngeal airway. Revision surgery allowing the angle to return to the neutral position was performed to attenuate the overflexion of the cervical position. After revision surgery, the upper airway obstruction disappeared. From the retrospective radiographic analysis, we suggest that the decrease of 18 degrees in the O-C2 angle causes the upper airway obstruction. On the extubation after occipito-cervical fusion, we should take care of the possibility of re-intubation and its difficulty based on the O-C2 angle.

Olprinone and colforsin daropate alleviate septic lung inflammation and apoptosis through CREB-independent activation of the Akt pathway.

Olprinone, a specific phosphodiesterase III inhibitor, and corforsin daropate, a direct adenylate cyclase activator, are now being used in critical conditions. We investigated whether their therapeutic use provides protection against septic acute lung injury (ALI) and mortality. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP) in BALB/c mice. Olprinone or colforsin daropate was continuously given through an osmotic pump that was implanted into the peritoneal cavity immediately following CLP. These treatments prevented the ALI development in CLP mice, as indicated by the findings that severe hypoxemia, increased pulmonary vascular permeability, and histological lung damage were strikingly remedied. Furthermore, continued administration of olprinone or colforsin daropate suppressed apoptosis induction in septic lungs and improved the survival of CLP mice. Olprinone and corforsin daropate enhanced Akt phosphorylation in septic lungs. Wortmannin, which inhibits the Akt upstream regulator phosphatidylinositol 3-kinase, abrogated the protective effects of olprinone and corforsin daropate on sepsis-associated lung inflammation and apoptosis. In vivo transfection of cyclic AMP response element binding protein (CREB) decoy oligodeoxynucleotide failed to negate the abilities of these agents to increase Akt phosphorylation and to inhibit IκBα degradation in septic lungs. These results demonstrate for the first time that CREB-independent Akt-mediated signaling is a critical mechanism contributing to the therapeutic effects of olprinone and corforsin daropate on septic ALI. Moreover, our data also suggest that these cyclic AMP-related agents, by blocking both nuclear factor-κB activation and apoptosis induction, may represent an effective therapeutic approach to the treatment of the septic syndrome.

Isoflurane pretreatment preserves adenosine triphosphate-sensitive K(+) channel function in the human artery exposed to oxidative stress caused by high glucose levels.

BACKGROUND: Adenosine triphosphate (ATP)-sensitive K(+) channels contribute to significant regulatory mechanisms related to organ blood flow in both physiological and pathological conditions. High glucose impairs arterial ATP-sensitive K(+) channel activity via superoxide production. However, the effects of anesthetics on this pathological process have not been evaluated in humans. In the present study, we investigated whether pretreatment with the volatile anesthetic isoflurane preserves ATP-sensitive K(+) channel activity in the human artery exposed to oxidative stress caused by high glucose. METHODS: All experiments were performed using human omental arteries without endothelium in the presence of d-glucose (5.5 mmol/L). Some arteries were treated with isoflurane (1.15% or 2.3%) in combination with d- or l-glucose (20 mmol/L) for 60 minutes, and then only isoflurane was discontinued. Relaxation and hyperpolarization of arterial segments in response to an ATP-sensitive K(+) channel opener levcromakalim were evaluated using the isometric force recording or electrophysiological study, respectively. Superoxide production was determined by dihydroethidium fluorescence. Immunohistochemical analysis for a subunit of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase p47phox was performed. Data were evaluated using repeated-measures analysis of variance or a factorial analysis of variance as appropriate, followed by Scheffé test. RESULTS: The ATP-sensitive K(+) channel antagonist glibenclamide (10(-6) mol/L) abolished relaxation induced by cumulative addition of levcromakalim (10(-8) to 10(-5) mol/L) in arteries treated with l-glucose (20 mmol/L). Incubation with d-glucose (20 mmol/L) impaired the vasorelaxation induced by levcromakalim. The selective NADPH oxidase NOX2 inhibitor gp91ds-tat (10(-6) mol/L) and pretreatment with isoflurane (1.15% and 2.3%) restored relaxation in response to levcromakalim in arteries treated with d-glucose (20 mmol/L). Isoflurane (2.3%), gp91ds-tat (10(-6) mol/L), and their combination similarly restored hyperpolarization in response to levcromakalim (3 × 10(-6) mol/L) in arteries treated with d-glucose (20 mmol/L). Along with these results, isoflurane (2.3%) reduced superoxide production and the intracellular mobilization of the cytosolic NOX2 subunit p47phox toward smooth muscle cell membrane in arteries treated with d-glucose (20 mmol/L). CONCLUSIONS: We have demonstrated for the first time a beneficial effect from the pretreatment with isoflurane on the isolated human artery. Pretreatment with isoflurane preserves ATP-sensitive K(+) channel activity in the human omental artery exposed to oxidative stress induced by high glucose, whereas the effect seems to be mediated by NADPH oxidase inhibition. Volatile anesthetics may protect human visceral arteries from malfunction caused by oxidative stress.

Beneficial effect of propofol on arterial adenosine triphosphate-sensitive K+ channel function impaired by thromboxane.

BACKGROUND: It is not known whether thromboxane A2 impairs adenosine triphosphate (ATP)-sensitive K channel function via increased production of superoxide in blood vessels and whether propofol as a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor restores this modification. METHODS: Rat aortas without endothelium were used for isometric force recording, measurements of membrane potential, and superoxide production and Western immunoblotting. Vasorelaxation to an ATP-sensitive K channel opener levcromakalim was obtained during contraction to phenylephrine (3 x 10(-7) M) or a thromboxane A2 analogue U46619 (3 x 10(-7) M). In some experiments, aortas were incubated with an ATP-sensitive K channel antagonist glibenclamide, a superoxide inhibitor Tiron, a nonselective NADPH oxidase inhibitor apocynin, a hydrogen peroxide scavenger catalase, a xanthine oxidase inhibitor allopurinol, a thromboxane receptor antagonist SQ29548 or propofol (3 x 10(-7) to 3 x 10(-6) M). RESULTS: Levcromakalim-induced vasorelaxation was abolished by glibenclamide in rings contracted with either vasoconstrictor agent. Tiron, apocynin, and propofol, but not catalase, augmented the vasodilator response as well as the hyperpolarization by levcromakalim in aortas contracted with U46619. Tiron, apocynin, SQ29548, and propofol, but not allopurinol, similarly reduced in situ levels of superoxide within aortic vascular smooth muscle exposed to U46619. Protein expression of a NADPH oxidase subunit p47phox increased in these arteries, and this augmentation was abolished by propofol. CONCLUSIONS: Thromboxane receptor activation induces vascular oxidative stress via NADPH oxidase, resulting in the impairment of ATP-sensitive K channel function. Propofol reduces this stress via inhibition of a NADPH oxidase subunit p47phox and, therefore, restores ATP-sensitive K channel function.