The mechanism of helium-induced preconditioning: a direct role for nitric oxide in rabbits

BACKGROUND: Helium produces preconditioning against myocardial infarction by activating prosurvival signaling, but whether nitric oxide (NO) generated by endothelial NO synthase plays a role in this phenomenon is unknown. We tested the hypothesis that NO mediates helium-induced cardioprotection in vivo. METHODS: Rabbits (n = 62) instrumented for hemodynamic measurement were subjected to a 30-min left anterior descending coronary artery occlusion and 3 h reperfusion, and received 0.9% saline (control) or three cycles of 70% helium-30% oxygen administered for 5 min interspersed with 5 min of an air-oxygen mixture before left anterior descending coronary artery occlusion in the absence or presence of pretreatment with the nonselective NOS inhibitor N-nitro-l-arginine methyl ester (L-NAME; 10 mg/kg), the selective inducible NOS inhibitor aminoguanidine hydrochloride (AG; 300 mg/kg), or selective neuronal NOS inhibitor 7-nitroindazole (7-NI; 50 mg/kg). In additional rabbits, the fluorescent probe 4,5-diaminofluroscein diacetate (DAF-2DA) and confocal laser microscopy were used to detect NO production in the absence or presence of helium with or without L-NAME pretreatment. RESULTS: Helium reduced (P < 0.05) infarct size (24% +/- 4% of the left ventricular area at risk; mean +/- sd) compared with control (46% +/- 3%). L-NAME, AG, and 7-NI did not alter myocardial infarct size when administered alone. L-NAME, but not 7-NI or AG, abolished helium-induced cardioprotection. Helium enhanced DAF-2DA fluorescence compared with control (26 +/- 8 vs 15 +/- 5 U, respectively). Pretreatment with L-NAME abolished these helium-induced increases in DAF-2DA fluorescence. CONCLUSIONS: The results indicate that cardioprotection by helium is mediated by NO that is probably generated by endothelial NOS in vivoope

Xenon preconditioning: the role of prosurvival signaling, mitochondrial permeability transition and bioenergetics in rats.

BACKGROUND: Similar to volatile anesthetics, the anesthetic noble gas xenon protects the heart from ischemia/reperfusion injury, but the mechanisms responsible for this phenomenon are not fully understood. We tested the hypothesis that xenon-induced cardioprotection is mediated by prosurvival signaling kinases that target mitochondria. METHODS: Male Wistar rats instrumented for hemodynamic measurements were subjected to a 30 min left anterior descending coronary artery occlusion and 2 h reperfusion. Rats were randomly assigned to receive 70% nitrogen/30% oxygen (control) or three 5-min cycles of 70% xenon/30% oxygen interspersed with the oxygen/nitrogen mixture administered for 5 min followed by a 15 min memory period. Myocardial infarct size was measured using triphenyltetrazolium staining. Additional hearts from control and xenon-pretreated rats were excised for Western blotting of Akt and glycogen synthase kinase 3 beta (GSK-3beta) phosphorylation and isolation of mitochondria. Mitochondrial oxygen consumption before and after hypoxia/reoxygenation and mitochondrial permeability transition pore opening were determined. RESULTS: Xenon significantly (P < 0.05) reduced myocardial infarct size compared with control (32 +/- 4 and 59% +/- 4% of the left ventricular area at risk; mean +/- sd) and enhanced phosphorylation of Akt and GSK-3beta. Xenon pretreatment preserved state 3 respiration of isolated mitochondria compared with the results obtained in the absence of the gas. The Ca(2+) concentration required to induce mitochondrial membrane depolarization was larger in the presence compared with the absence of xenon pretreatment (78 +/- 17 and 56 +/- 17 microM, respectively). The phosphoinositol-3-kinase-kinase inhibitor wortmannin blocked the effect of xenon on infarct size and respiration. CONCLUSIONS: These results indicate that xenon preconditioning reduces myocardial infarct size, phosphorylates Akt, and GSK-3beta, preserves mitochondrial function, and inhibits Ca(2+)-induced mitochondrial permeability transition pore opening. These data suggest that xenon-induced cardioprotection occurs because of activation of prosurvival signaling that targets mitochondria and renders them less vulnerable to ischemia-reperfusion injuryope

Spinal and Supraspinal Changes in Vitamin D3 Up-regulated Protein 1 (VDUP1) Gene Expression after Spinal Cord Injury

Background: Vitamin D3 up-regulated protein 1 (VDUP1) gene is known to be a novel member of the early response genes and an oxidative stress mediator. This study was designed to elucidate VDUP1 expression and its involvement in central sensitization after spinal cord injury (SCI). Methods: Contusion injury was produced at spinal segment T10 (20 mm drop, 10 g rod) in adult male Sprague-Dawley rats (250-300 g). Withdrawal responses were measured using von Frey filaments and acetone on the 1st, 3rd and 7th days after SCI. The expressions of VDUP1 gene in the brain and in the cervical and lumbar spine were examined by immunohistochemistry on the 1st, 3rd and 7th day after SCI. Results: VDUP1 gene was detected in a few oligodendrocytes in the spinal cord and in the brain of control rats. VDUP1 gene expression increased in most of the neurons and ependymal cells in the central canal of the injured (lumbar) spinal cord 1 day after SCI. This expression gradually decreased in majority of cells from day 1 to day 7 after SCI. VDUP1 gene expression was also observed to be increased 1 day after SCI, and gradually to decrease from 1 day to 7 days after SCI. The neurons in the intact (cervical) spinal cord VDUP1 gene expression increases maximally 3 days after SCI in the cerebral cortex and the thalamus. Neuropathic pain behavior was triggered by the plantar surface of the fore foot after SCI. Conclusions: These results show that the VDUP1 gene may be an early modulator of transneuronal stress response after SCI, and to be related to the central sensitization of neuropathic pain behavior after SCI.ope

The Effect of Simultaneous and Alternative Cardioplegia Delivery on Right Ventricular Preservation in Patients Undergoing Right Coronary Artery Bypass Graft Surgery

Background: Most surgeons prefer delivering cardioplegia alternatively via the aortic root and coronary sinus in patients undergoing coronary artery bypass graft surgery (CABG). Recently, some surgeons have delivered cardioplegia via the grafted vessel to the obstructed right coronary artery in order to preserve right ventricular function whenever retrograde cardioplegia is delivered. Thus, we have compared the effect on right ventricular preservation between the forementioned two methods after cardiopulmonary bypass in patients undergoing a right CABG. Methods: Twenty-eight patients undergoing an elective CABG with significant right coronary artery obstructive disease were allocated into 2 groups. In the alternative cardioplegia delivery group (A-group), cold blood cardioplegia was delivered via the aortic root and coronary sinus alternatively. In the simultaneous cardioplegia delivery group (S-group), cold blood cardioplegia was delivered via the coronary sinus and grafted vessel to the obstructed right coronary artery simultaneously. Hemodynamic measurements were obtained pre-bypass, at pericardial closure and at sternal closure. Data recorded included right ventricular ejection fraction, right ventricular volume index and right and left ventricular hemodynamics. Results: There was no significant difference in the right ventricular ejection fraction between the two groups at pre-bypass, pericardial closure and sternal closure. In both groups, the right ventricular ejection fraction and cardiac index were not decreased, and the left ventricular ejection fraction was higher at pericardial closure than pre-bypass. However, in both groups, there was a decrease in the right andleft ventricular stroke work index and right ventricular stroke volume index at sternal closure. Conclusions: We have concluded that simultaneous cardioplegia delivery via the coronary sinus and grafted vessel to the obstructed right coronary artery was not superior to the alternative cardioplegia delivery via the aortic root and coronary sinus for preservation of right ventricular function in patients undergoing a right CABG.ope

Inhibition of glycogen synthase kinase or the apoptotic protein p53 lowers the threshold of helium cardioprotection in vivo: the role of mitochondrial permeability transition

BACKGROUND: Prosurvival signaling kinases inhibit glycogen synthase kinase-3beta (GSK-3beta) activity and stimulate apoptotic protein p53 degradation. Helium produces cardioprotection by activating prosurvival kinases, but whether GSK and p53 inhibition mediate this process is unknown. We tested the hypothesis that inhibition of GSK or p53 lowers the threshold of helium cardioprotection via a mitochondrial permeability transition pore (mPTP)-dependent mechanism. METHODS: Rabbits (n = 85) instrumented for hemodynamic measurement and subjected to a 30 min left anterior descending coronary artery (LAD) occlusion and 3 h reperfusion received 0.9% saline (control), or 1, 3, or 5 cycles of 70% helium-30% oxygen administered for 5 min interspersed with 5 min of an air-oxygen mixture (fraction of inspired oxygen concentration = 0.30) before LAD occlusion. Other rabbits received the GSK inhibitor SB 216763 (SB21; 0.2 or 0.6 mg/kg), the p53 inhibitor pifithrin-alpha (PIF; 1.5 or 3.0 mg/kg), or SB21 (0.2 mg/kg) or PIF (1.5 mg/kg) plus helium (1 cycle) before LAD occlusion in the presence or absence of the mPTP opener atractyloside (5 mg/kg). RESULTS: Helium reduced (P < 0.05) myocardial infarct size (35 +/- 6 [n = 7], 25 +/- 4 [n = 7], and 20 +/- 3% [n = 6] of area at risk, 1, 3, and 5 cycles, respectively) compared with control (44 +/- 6% [n = 7]). SB21 (0.6 [n = 7] but not 0.2 mg/kg [n = 6]) and PIF (3.0 [n = 6] but not 1.5 mg/kg [n = 7]) also reduced necrosis. SB21 (0.2 mg/kg) or 1.5 mg/kg PIF (1.5 mg/kg) plus helium (1 cycle; n = 6 per group) decreased infarct size to an equivalent degree as three cycles of helium alone, and this cardioprotection was blocked by atractyloside (n = 7 per group). CONCLUSIONS: Inhibition of GSK or p53 lowers the threshold of helium-induced preconditioning via a mPTP-dependent mechanism in vivoope

Isoflurane differentially modulates mitochondrial reactive oxygen species production via forward versus reverse electron transport flow: implications for preconditioning

BACKGROUND: Reactive oxygen species (ROS) mediate the effects of anesthetic precondition to protect against ischemia and reperfusion injury, but the mechanisms of ROS generation remain unclear. In this study, the authors investigated if mitochondria-targeted antioxidant (mitotempol) abolishes the cardioprotective effects of anesthetic preconditioning. Further, the authors investigated the mechanism by which isoflurane alters ROS generation in isolated mitochondria and submitochondrial particles. METHODS: Rats were pretreated with 0.9% saline, 3.0 mg/kg mitotempol in the absence or presence of 30 min exposure to isoflurane. Myocardial infarction was induced by left anterior descending artery occlusion for 30 min followed by reperfusion for 2 h and infarct size measurements. Mitochondrial ROS production was determined spectrofluorometrically. The effect of isoflurane on enzymatic activity of mitochondrial respiratory complexes was also determined. RESULTS: Isoflurane reduced myocardial infarct size (40 ± 9% = mean ± SD) compared with control experiments (60 ± 4%). Mitotempol abolished the cardioprotective effects of anesthetic preconditioning (60 ± 9%). Isoflurane enhanced ROS generation in submitochondrial particles with nicotinamide adenine dinucleotide (reduced form), but not with succinate, as substrate. In intact mitochondria, isoflurane enhanced ROS production in the presence of rotenone, antimycin A, or ubiquinone when pyruvate and malate were substrates, but isoflurane attenuated ROS production when succinate was substrate. Mitochondrial respiratory experiments and electron transport chain complex assays revealed that isoflurane inhibited only complex I activity. CONCLUSIONS: The results demonstrated that isoflurane produces ROS at complex I and III of the respiratory chain via the attenuation of complex I activity. The action on complex I decreases unfavorable reverse electron flow and ROS release in myocardium during reperfusionope

Sugammadex versus neostigmine reversal of moderate rocuronium-induced neuromuscular blockade in Korean patients

BACKGROUND: Rapid and complete reversal of neuromuscular blockade (NMB) is desirable at the end of surgery. Sugammadex reverses rocuronium-induced NMB by encapsulation. It is well tolerated in Caucasian patients, providing rapid reversal of moderate (reappearance of T2) rocuronium-induced NMB. We investigated the efficacy and safety of sugammadex versus neostigmine in Korean patients. METHODS: This randomized, safety assessor-blinded trial (NCT01050543) included Korean patients undergoing general anesthesia. Rocuronium 0.6 mg/kg was given prior to intubation with maintenance doses of 0.1-0.2 mg/kg as required. Patients received sugammadex 2.0 mg/kg or neostigmine 50 µg/kg with glycopyrrolate 10 µg/kg to reverse the NMB at the reappearance of T2, after the last rocuronium dose. The primary efficacy endpoint was the time from sugammadex or neostigmine administration to recovery of the train-of-four (TOF) ratio to 0.9. The safety of these medications was also assessed. RESULTS: Of 128 randomized patients, 118 had evaluable data (n = 59 in each group). The geometric mean (95% confidence interval) time to recovery of the TOF ratio to 0.9 was 1.8 (1.6, 2.0) minutes in the sugammadex group and 14.8 (12.4, 17.6) minutes in the neostigmine group (P < 0.0001). Sugammadex was generally well tolerated, with no evidence of residual or recurrence of NMB; four patients in the neostigmine group reported adverse events possibly indicative of inadequate NMB reversal. CONCLUSIONS: Sugammadex was well tolerated and provided rapid reversal of moderate rocuronium-induced NMB in Korean patients, with a recovery time 8.1 times faster than neostigmine. These results are consistent with those reported for Caucasian patients.ope

Propofol and Involuntary Movements in Children: The Differences on Infusion Rates

Background: Although the pro-convulsant or anticonvulsant properties of propofol remain a matter of controversy, it is evident that propofol can produce involuntary movement. Such movement is a relatively common side effect, especially in children, and may be dose-related or injection rate-related. The goal of this study was to evaluate the effect of injection rate upon involuntary movement during propofol induction in children. Methods: Children (age 3-14 yr) undergoing elective Eye and ENT surgery were randomly allocated to one of 4 groups based on the propofol injection rate (A, manual/15 s; B, 360 ml/hr; C, 200 ml/hr, D, 100 ml/hr) using a manual injection method and syringe pumps. No premedication was used. The induction dosage of propofol was 3 mg/kg in all groups. Fentanyl 1 mcg/kg and 1% lidocaine 1-2 ml were given I.V. before propofol. Involuntary movement was graded 0-2 on severity. The infused dose of propofol at movement was measured. Movement due to pain or mask fitting was not regarded as an involuntary movement. All results were analyzed using the Chi-Square Test and ANOVA. Results: 595 children were studied. Age, gender, and weight were similar in the 4 groups. Involuntary movements were apparent in 179 (30.1%) of the 595 subjects. Movements were significantly less in group A (12.4%) and B (16.4%) compared to group C (46.6%) and D (45.3%). The grades of movement were not different among the 4 groups. The durations of movement in group A and B were significantly short compared to group C and D. The infused dose of propofol (mg/kg) at movement was higher in group C (2.65 ± 0.62) than in A (1.99 ± 0.62) and B (2.43 ± 0.78). There were no significant hemodynamic and SPO2 changes during and after the propofol injection. Conclusions: We concluded that slow injection may increase the incidence of involuntary movement during propofol induction in children. Since the bolus injection rates are usually slow in most syringe pumps, manual injection for 10-15 s may be a better choice for smoother induction, as it requires fewer interventions to prevent venous catheter displacement in children.ope

Benefits of a ProSeal Laryngeal Mask Airway in a Laparoscopic Cholecystectomy

Background: The ProSeal laryngeal mask airway (PLMA) is a new laryngeal mask device with a larger cuff and a drainage tube. This study was designed to assess the usefulness and the safety of the PLMA in a laparoscopic cholecystectomy. Methods: Forty patients undergoing a laparoscopic cholecystectomy were randomly allocated to two groups; an endotracheal tube (ETT) group or a PLMA group. Anesthesia was induced with intravenous fentanyl and propofol and maintained with TCI-propofol. Blood pressure, heart rate, peak inspiratory pressure, peripheral O2 saturation (SpO2), end-tidal CO2 tension (PETCO2) and PaCO2 was measured during the operation. The incidence of gastric content regurgitation and gross pulmonary aspiration were evaluated. Postoperatively, SpO2, the visual analogue scale (VAS) of pain, nausea and vomiting (PONV), and sore throat were evaluated at 30 minutes intervals in post-anesthetic care unit (PACU) and at night. Results: There were no significant differences in intraoperative PIP, SpO2, PETCO2, postoperative SpO2, VAS scores, PONV, and sore throat between the two groups. Gross pulmonary aspiration was not found in either group, but minimal gastric regurgitation occurred in 2 cases of the ETT group and 1 case of the PLMA group. Conclusions: We concluded that there were no differences in patient safety and adequate ventilation for a laparoscopic cholecystectomy between the ETT group and PLMA group. Moreover, there were no increases in blood pressure and heart rate in PLMA group during insertion/intubation.ope

Reactive Oxygen Species and Mitochondrial Adenosine Triphosphate-Regulated Potassium Channels Mediate Helium-Induced Preconditioning Against Myocardial Infarction In Vivo

OBJECTIVES: Helium produces preconditioning by activating prosurvival kinases, but the roles of reactive oxygen species (ROS) or mitochondrial adenosine triphosphate-regulated potassium (K(ATP)) channels in this process are unknown. The authors tested the hypothesis that ROS and mitochondrial K(ATP) channels mediate helium-induced preconditioning in vivo. DESIGN: A randomized, prospective study. SETTING: A university research laboratory. PARTICIPANTS: Male New Zealand white rabbits. INTERVENTIONS: Rabbits (n = 64) were instrumented for the measurement of systemic hemodynamics and subjected to a 30-minute left anterior descending coronary artery (LAD) occlusion and 3 hours of reperfusion. In separate experimental groups, rabbits (n = 7 or 8 per group) were randomly assigned to receive 0.9% saline (control) or 3 cycles of 70% helium-30% oxygen administered for 5 minutes interspersed with 5 minutes of an air-oxygen mixture before LAD occlusion with or without the ROS scavengers N-acetylcysteine (NAC; 150 mg/kg) or N-2 mercaptoproprionyl glycine (2-MPG; 75 mg/kg), or the mitochondrial K(ATP) antagonist 5-hydroxydecanoate (5-HD; 5 mg/kg). Statistical analysis of data was performed with analysis of variance for repeated measures followed by Bonferroni's modification of a Student t test. MEASUREMENTS AND MAIN RESULTS: The myocardial infarct size was determined by using triphenyltetrazolium chloride staining and presented as a percentage of the left ventricular area at risk. Helium significantly (p < 0.05) reduced infarct size (23 +/- 4% of the area at risk; mean +/- standard deviation) compared with control (46 +/- 3%). NAC, 2-MPG, and 5-HD did not affect irreversible ischemic injury when administered alone (49 +/- 5%, 45 +/- 6%, and 45 +/- 3%), but these drugs blocked reductions in infarct size produced by helium (45 +/- 4%, 45 +/- 2%, and 44 +/- 3%). CONCLUSIONS: The results suggest that ROS and mitochondrial K(ATP) channels mediate helium-induced preconditioning in vivo.ope