Mechanism for resveratrol-induced cardioprotection against reperfusion injury involves glycogen synthase kinase 3beta and mitochondrial permeability transition pore.

Resveratrol pretreatment can protect the heart by inducing pharmacological preconditioning. Whether resveratrol protects the heart when applied at reperfusion remains unknown. We examined the effect of resveratrol on myocardial infarct size when given at reperfusion and investigated the mechanism underlying the effect. Isolated rat hearts were subjected to 30 min ischemia followed by 2 h of reperfusion, and myocardial samples were collected from the risk zone for Western blot analysis. Mitochondrial swelling was spectrophotometrically measured as a decrease in absorbance at 520 nm (A(520)). Resveratrol reduced infarct size and prevented cardiac mitochondrial swelling. Resveratrol enhanced GSK-3beta phosphorylation upon reperfusion, an effect that was mediated by the cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG) pathway. Resveratrol translocated GSK-3beta from cytosol to mitochondria via the cGMP/PKG pathway. Further studies showed that mitochondrial GSK-3beta was co-immunoprecipitated with cyclophilin D but not with VDAC (voltage dependent anion channel) or ANT (adenine nucleotide translocator). These data suggest that resveratrol prevents myocardial reperfusion injury presumably by targeting the mPTP through translocation of GSK-3beta from cytosol to mitochondria. Translocated GSK-3beta may ultimately interact with cyclophilin D to modulate the mPTP opening.

Anesthesia-related perioperative adverse events during in-patient and out-patient procedures.

PURPOSE: This paper aims to determine the one-year incidence of, and risk factors for, perioperative adverse events during in-patient and out-patient anesthesia-assisted procedures. DESIGN/METHODOLOGY/APPROACH: A quality assurance database was the primary data source. Outcome variables were death and the occurrence of any adverse event. Risk factors were ASA physical status (PS), age, duration and type of anesthesia care, number of operating rooms running, concurrency level and medical staff. Data were stratified by in-patient or out-patient, surgical (e.g. thoracotomy) or non-surgical (e.g. electroconvulsive therapy), and were analyzed using Chi square, Fisher's exact test and generalized estimating equations. FINDINGS: Of 27,970 procedures, 49.8 percent were out-patient and greater than 80 percent were surgical. For surgical procedures, adverse event rates were higher for in-patient than out-patient procedures (2.11 percent vs. 1.45 percent; p < 0.001). For non-surgical procedures, adverse event rates were similar for in-patients and out-patients (0.54 percent vs. 0.36 percent). The types of adverseevents differed for in-patient and out-patient surgical procedures (p < 0.001), but not for non-surgical procedures. ASA PS, age, duration of anesthesia care, anesthesia type and medical staff assigned to the case were each associated with adverse event rates, but the association depended on the type of procedure. PRACTICAL IMPLICATIONS: In-patient and out-patient surgical procedures differ in the incidence of perioperative adverse events, and in risk factors, suggesting a need to develop separate monitoring strategies. ORIGINALITY/VALUE: The paper is the first to assess perioperative adverse events amongst in-patient and out-patient procedures.

Exogenous zinc protects cardiac cells from reperfusion injury by targeting mitochondrial permeability transition pore through inactivation of glycogen synthase kinase-3beta.

The purpose of this study was to determine whether exogenous zinc prevents cardiac reperfusion injury by targeting the mitochondrial permeability transition pore (mPTP) via glycogen synthase kinase-3beta (GSK-3beta). The treatment of cardiac H9c2 cells with ZnCl2 (10 microM) in the presence of zinc ionophore pyrithione for 20 min significantly enhanced GSK-3beta phosphorylation at Ser9, indicating that exogenous zinc can inactivate GSK-3beta in H9c2 cells. The effect of zinc on GSK-3beta activity was blocked by the phosphatidylinositol 3-kinase (PI3K) inhibitor LY-294002 but not by the mammalian target of rapamycin (mTOR) inhibitor rapamycin or the PKC inhibitor chelerythrine, implying that PI3K but not mTOR or PKC accounts for the action of zinc. In support of this interpretation, zinc induced a significant increase in Akt but not mTOR phosphorylation. Further experiments found that zinc also increased mitochondrial GSK-3beta phosphorylation. This may indicate an involvement of the mitochondria in the action of zinc. The effect of zinc on mitochondrial GSK-3beta phosphorylation was not altered by the mitochondrial ATP-sensitive K+ channel blocker 5-hydroxydecanoic acid. Zinc applied at reperfusion reduced cell death in cells subjected to simulated ischemia/reperfusion, indicating that zinc can prevent reperfusion injury. However, zinc was not able to exert protection in cells transfected with the constitutively active GSK-3beta (GSK-3beta-S9A-HA) mutant, suggesting that zinc prevents reperfusion injury by inactivating GSK-3beta. Cells transfected with the catalytically inactive GSK-3beta (GSK-3beta-KM-HA) also revealed a significant decrease in cell death, strongly supporting the essential role of GSK-3beta inactivation in cardioprotection. Moreover, zinc prevented oxidant-induced mPTP opening through the inhibition of GSK-3beta. Taken together, these data suggest that zinc prevents reperfusion injury by modulating the mPTP opening through the inactivation of GSK-3beta. The PI3K/Akt signaling pathway is responsible for the inactivation of GSK-3beta by zinc.

Postconditioning prevents reperfusion injury by activating delta-opioid receptors.

BACKGROUND: While postconditioning has been proposed to protect the heart by targeting the mitochondrial permeability transition pore (mPTP), the detailed mechanism underlying this action is unknown. The authors hypothesized that postconditioning stimulates opioid receptors, which in turn protect the heart from reperfusion injury by targeting the mPTP. METHODS: Rat hearts (both in vivo and in vitro) were subjected to 30 min of ischemia and 2 h of reperfusion. Postconditioning was elicited by six cycles of 10-s reperfusion and 10-s ischemia. To measure nitric oxide concentration, cardiomyocytes loaded with 4-amino-5-methylamino-2',7'-difluorofluorescein were imaged using confocal microscopy. Mitochondrial membrane potential was determined by loading cardiomyocytes with tetramethylrhodamine ethyl ester. RESULTS: In open chest rats, postconditioning reduced infarct size, an effect that was reversed by both naloxone and naltrindole. The antiinfarct effect of postconditioning was also blocked by the mPTP opener atractyloside. In isolated hearts, postconditioning reduced infarct size. Morphine mimicked postconditioning to reduce infarct size, which was abolished by both naltrindole and atractyloside. N-nitro-l-arginine methyl ester and guanylyl cyclase inhibitor 1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one blocked the action of morphine. Further experiments showed that morphine produces nitric oxide in cardiomyocytes by activating delta-opioid receptors. Moreover, morphine could prevent hydrogen peroxide-induced collapse of mitochondrial membrane potential in cardiomyocytes, which was reversed by naltrindole, N-nitro-l-arginine methyl ester, and the protein kinase G inhibitor KT5823. CONCLUSIONS: Postconditioning protects the heart by targeting the mPTP through activation of delta-opioid receptors. The nitric oxide-cyclic guanosine monophosphate-protein kinase G pathway may account for the effect of postconditioning on the mPTP opening.

Postoperative mortality after inpatient surgery: Incidence and risk factors.

PURPOSE: This study determined the incidence of and identified risk factors for 48 hour (h) and 30 day (d) postoperative mortality after inpatient operations. METHODS: A retrospective cohort study was conducted using Anesthesiology's Quality Indicator database as the main data source. The database was queried for data related to the surgical procedure, anesthetic care, perioperative adverse events, and birth/death/operation dates. The 48 h and 30 d cumulative incidence of postoperative mortality was calculated and data were analyzed using Chi-square or Fisher's exact test and generalized estimating equations. RESULTS: The 48 h and 30 d incidence of postoperative mortality was 0.57% and 2.1%, respectively. Higher American Society of Anesthesiologists physical status scores, extremes of age, emergencies, perioperative adverse events and postoperative Intensive Care Unit admission were identified as risk factors. The use of monitored anesthesia care or general anesthesia versus regional or combined anesthesia was a risk factor for 30 d postoperative mortality only. Time under anesthesia care, perioperative hypothermia, trauma, deliberate hypotension and invasive monitoring via arterial, pulmonary artery or cardiovascular catheters were not identified as risk factors. CONCLUSIONS: Our findings can be used to track postoperative mortality rates and to test preventative interventions at our institution and elsewhere.

NO mobilizes intracellular Zn2+ via cGMP/PKG signaling pathway and prevents mitochondrial oxidant damage in cardiomyocytes.

OBJECTIVE: Our aim was to determine if NO prevents mitochondrial oxidant damage by mobilizing intracellular free zinc (Zn(2+)). METHODS: Zn(2+) levels were determined by imaging enzymatically isolated adult rat cardiomyocytes loaded with Newport Green DCF. Mitochondrial membrane potential (DeltaPsi(m)) was assessed by imaging cardiomyocytes loaded with tetramethylrhodamine ethyl ester (TMRE). RESULTS: S-nitroso-N-acetylpenicillamine (SNAP) dramatically increased Zn(2+), which was blocked by both ODQ and NS2028, two specific inhibitors of guanylyl cyclase. The protein kinase G (PKG) inhibitor KT5823 blocked the effect of SNAP while the PKG activator 8-Br-cGMP mimicked the action of SNAP, indicating that the cGMP/PKG pathway is responsible for the effect of SNAP. The increased Zn(2+) was prevented by 5-hydroxydecanoate (5HD) but was mimicked by diazoxide, implying that mitochondrial K(ATP) channel opening may account for this effect. Since chelation of Zn(2+) blocked the preventive effect of SNAP on H(2)O(2)-induced loss of DeltaPsi(m) and exogenous zinc (1 microM ZnCl(2)) prevented dissipation of DeltaPsi(m), Zn(2+) may play a critical role in the protective effect of NO. The MEK (mitogen-activated protein kinase or extracellular signal-regulated kinase) inhibitor PD98059 blocked the preventive effects of SNAP and zinc on DeltaPsi(m), indicating that extracellular signal-regulated kinase (ERK) mediates the protective effect of both these compounds on mitochondrial oxidant damage. A Western blot analysis further showed that ZnCl(2) significantly enhances phosphorylation of ERK, confirming the involvement of ERK in the action of Zn(2+). CONCLUSIONS: In isolated cardiomyocytes, NO mobilizes endogenous zinc by opening mitochondrial K(ATP) channels through the cGMP/PKG pathway. In these cells, Zn(2+) may be an important mediator of the action of NO on the mitochondrial death pathway.

IB-MECA and cardioprotection.

The adenosine A(3) receptor plays an important role in ischemic preconditioning. Activation of the adenosine A(3) receptor with its agonists induces both early and late pharmacological preconditioning through various mechanisms. As the first potent and selective adenosine A(3) receptor agonist, IB-MECA (N(6)-(3-iodobenzyl)-adenosine-5'-N-methylcarboxamide) has been demonstrated to induce cardioprotection against myocardial ischemia/reperfusion injury when given before onset of ischemia by triggering pharmacological preconditioning. More importantly, IB-MECA can also protect the heart even when administered at the onset of reperfusion after ischemia, indicating a strong likelihood that the drug may be useful for the treatment of patients with acute myocardial infarction. However, since IB-MECA has been reported to have lethal effects at higher concentrations, and may cause systemic hypertension in some species, further studies are needed to find the best treatment strategy to increase its therapeutic potential.

Elastic tourniquet technique for decompression of extremity compartment syndrome.

Compartment syndrome of the extremities is usually associated with direct trauma and often requires surgical fasciotomy to avert potential complications and morbidity. We present a case of upper extremity compartment syndrome resulting from pressurized infusion of autologous whole blood, in which fasciotomy was avoided by the application of a simple and effective technique using an elastic Esmarch bandage. Guidelines for surgical fasciotomy and the hazards associated with pressurized infusion of fluids in the anesthetized patient are discussed.