Exercise training confers sustainable protection against ischemia/reperfusion injury. However, the mechanism by which this process occurs is not fully understood. Previously, it was shown that β₃-adrenergic receptors (β₃-ARs) play a critical role in regulating the activation of endothelial nitric oxide synthase (eNOS) in response to exercise and play a critical role in exercise-mediated cardioprotection. Intriguingly, a deficiency in β₃-ARs led to increased myocardial injury following exercise training. The purpose of the current study was to determine mechanisms by which β₃-ARs are linked to eNOS activation and to determine the mechanism responsible for the exacerbated ischemia/reperfusion injury displayed by β₃-AR deficient (β₃-AR KO) mice after exercise training. Wild-type (n = 37) and β₃-AR KO ( n = 40) mice were subjected to voluntary wheel running for 4 weeks. Western blot analysis revealed that neither protein kinase B nor protein kinase A linked β₃-ARs to eNOS following exercise training. However, analysis revealed a role for AMP-activated protein kinase (AMPK). Specifically, exercise training increased the phosphorylation of AMPK in the hearts of wild-type mice, but failed to do so in the hearts of β₃-AR KO mice. Additional studies revealed that exercise training rendered eNOS less coupled and increased NOS-dependent superoxide levels in β₃-AR KO mice. Finally, supplementing β₃-AR KO mice with the eNOS coupler, tetrahydrobiopterin, during the final week of exercise training reduced myocardial infarction. These findings provide important information that exercise training protects the heart in the setting of myocardial ischemia/reperfusion injury by activating and coupling eNOS via the stimulation of a β₃-AR-AMPK signaling pathway.

The therapeutic effects of hydrogen-rich saline (HRS) have been reported for a wide range of diseases mainly via selectively reducing the amount of reactive oxygen species. Oxidative stress plays an important role in the pathogenesis of uveitis and endotoxin-induced uveitis (EIU). In this study, we investigated whether HRS can mitigate EIU in rats. Sprague-Dawley rats were randomly divided into Norm group, Model group, HRS group, dexamethasone (DEX) group, and rats in the latter three groups were injected with equal amount of lipopolysaccharide (LPS) to induce EIU of different severities (by 1 mg/kg of LPS, or 1/8 mg/kg of LPS). Rats in HRS group were injected with HRS intraperitoneally at three different modes to purse an ameliorating effect of EIU (10 mL/kg of HRS immediately after injection of 1 mg/kg of LPS, 20 mL/kg of HRS once a day for 1 week before injection of 1 mg/kg of LPS and at 0, 0.5, 1, 2, 6, 8, 12 hours after LPS administration, or 20 mL/kg of HRS once a day for 1 week before injection of 1/8 mg/kg of LPS, and at 0, 0.5, 1, 2, 6, 8, 12, 24 hours and once a day for 3 weeks after LPS administration). Rats of DEX group were injected with 1 mL/kg of DEX solution intraperitoneally immediately after LPS administration. Rats in Norm and Model groups did not receive any treatment. All rats were examined under slit lamp microscope and graded according to the clinical signs of uveitis. Electroretinogram, quantitative analysis of protein in aqueous humor (AqH) and histological examination of iris and ciliary body were also carried out. Our results showed that HRS did not obviously ameliorate the signs of uveitis under slit lamp examination and the inflammatory cells infiltration around iris and cilliary body of EIU induced by 1 mg/kg or 1/8 mg/kg of LPS (P > 0.05), while DEX significantly reduced the inflammation reflected by the above two indicators (P < 0.05). The impaired retinal function of mild EIU induced by 1/8 mg/kg of LPS, showed by delay of peak time of b-wave of Dark adapted 3.0 electroretinogram, was not significantly restored by HRS (P > 0.05), while DEX had an obvious therapeutic effect (P < 0.05). However, HRS exerted an inhibition trend on elevation of protein in AqH of EIU induced by 1 mg/kg of LPS, and significantly reduced the increasing amount of protein in AqH of mild EIU induced by 1/8 mg/kg of LPS (P < 0.05). In conclusion, HRS could not obviously mitigate EIU in rats, while it could inhibit the elevation of AqH protein.

Sevoflurane and isoflurane are volatile halogenated ether widely used in anesthesia. Both have comparable potency and easy titratability but sevoflurane has lower pungency and results in faster patient recovery. Isoflurane, however, is more affordable. The nephrotoxicity of sevoflurane is undisputed but studies on isoflurane nephrotoxicity are lacking. The objective of this paper is to determine the overall nephrotoxicity profile of sevoflurane and isoflurane in donor nephrectomy patients using the renal function markers - nuclear glomerular filtration rate (GFR), serum creatinine, urine protein-to-creatinine ratio, proteinuria, and glucosuria. A randomized comparative study of postoperative renal functions in donor nephrectomy patients who had received either low-flow (< 1 L/min) sevoflurane or isoflurane were analyzed. The renal parameters were repeated 72 hours post anesthesia. Forty-seven subjects (46%) were randomized to receive isoflurane while fifty-five received sevoflurane (54%). Between the two anesthetic groups, there was no significant difference in terms of serum creatinine, total GFR, or nuclear GFR. There was a statistically higher proportion of patients with urine protein-to-creatinine ratios of 0.2 and above in the isoflurane group (64% vs. 38%), while more patients in the sevoflurane group had ratios above 0.2 (62% vs. 36%, P < 0.05). The type of anesthetic agent was not an independent predictor of increasing serum creatinine, total GFR and urine protein-to-creatinine ratio and nuclear GFR. In conclusion, the overall nephrotoxicity profile of sevoflurane and isoflurane-treated donor nephrectomy patients is minimal.

Argon (Ar) is a noble gas with known organoprotective effects in rodents and in vitro models. In a previous study we failed to find a postconditioning effect of Ar during ex vivo lung perfusion (EVLP) on warm-ischemic injury in a porcine model. In this study, we further investigated a prolonged exposure to Ar to decrease cold ischemia-reperfusion injury after lung transplantation in a porcine model with EVLP assessment. Domestic pigs (n = 6/group) were pre-conditioned for 6 hours with 21% O ₂ and 79% N ₂ (CONTR) or 79% Ar (ARG). Subsequently, lungs were cold flushed and stored inflated on ice for 18 hours inflated with the same gas mixtures. Next, lungs were perfused for 4 hours on EVLP (acellular) while ventilated with 12% O ₂ and 88% N ₂ (CONTR group) or 88% Ar (ARG group). The perfusate was saturated with the same gas mixture but with the addition of CO ₂ to an end-tidal CO ₂ of 35-45 mmHg. The saturated perfusate was drained and lungs were perfused with whole blood for an additional 2 hours on EVLP. Evaluation at the end of EVLP did not show significant effects on physiologic parameters by prolonged exposure to Ar. Also wet-to-dry weight ratio did not improve in the ARG group. Although in other organ systems protective effects of Ar have been shown, we did not detect beneficial effects of a high concentration of Ar on cold pulmonary ischemia-reperfusion injury in a porcine lung model after prolonged exposure to Ar in this porcine model with EVLP assessment.

Carbon monoxide (CO) formed endogenously is considered to be cytoprotective, and the vast majority of CO formation is attributed to the degradation of heme by heme oxygenases-1 and -2 (HO-1, HO-2). Previously, we observed that brain microsomes containing HO-2 produced many-fold more CO in the presence of menadione and its congeners; herein we explored these observations further. We determined the effects of various drugs on CO production of rat brain microsomes and recombinant human cytochrome P450 reductase (CPR); CO was measured by gas chromatography with reductive detection. Brain microsomes of Sprague-Dawley rats or recombinant human cytochrome P450 reductase (CPR) were incubated with NADPH and various drugs in closed vials in phosphate buffer at pH 7.4 and 37°C. After 15 minutes, the reaction was stopped by cooling in dry ice, and the headspace gas was analyzed for CO production using gas chromatography with reductive (mercuric oxide) detection. We observed drug-enhanced CO production in the presence of both microsomes and recombinant CPR alone; the presence of HO was not required. A range of structurally diverse drugs were capable of amplifying this CO formation; these molecules had structures consistent with redox cycling capability. The addition of catalase to a reaction mixture, that contained activating drugs, inhibited the production of CO. Drug-enhanced CO formation can be catalyzed by CPR. The mechanism of CPR activation was not through classical drug-receptor mediation. Redox cycling may be involved in the drug-induced amplification of CO production by CPR through the production of reactive oxygen species.

Isoflurane, a volatile and inhalational anesthetic, has been extensively used in perioperative period for several decades. A large amount of experimental studies have indicated that isoflurane exhibits neuroprotective properties when it is administrated before or after (pre-conditioning and post-conditioning) neurodegenerative diseases (e.g., hypoxic ischemia, stroke and trauma). Multiple mechanisms are involved in isoflurane induced neuroprotection, including activation of glycine and γ-aminobutyric acid receptors, antagonism of ionic channels and alteration of the function and activity of other cellular proteins. Although neuroprotection provided by isoflurane is observed in many animal studies, convincing evidence is lacking in human trials. Therefore, there is still a long way to go before translating its neuroprotective properties into clinical practice.

Molecular oxygen (O₂) is essential to brain function and mechanisms necessary to regulate variations in delivery or utilization of O₂ are crucial to support normal brain homeostasis, physiology and energy metabolism. Any imbalance in cerebral tissue partial pressure of O₂ (pO₂) levels may lead to pathophysiological complications including increased reactive O₂ species generation leading to oxidative stress when tissue O₂ level is too high or too low. Accordingly, the need for oximetry methods, which assess cerebral pO₂ in vivo and in real time, is imperative to understand the role of O₂ in various metabolic and disease states, including the effects of treatment and therapy options. In this review, we provide a brief overview of the common in vivo oximetry methodologies for measuring cerebral pO₂ . We discuss the advantages and limitations of oximetry methodologies to measure cerebral pO₂ in vivo followed by a more in-depth review of electron paramagnetic resonance oximetry spectroscopy and imaging using several examples of current electron paramagnetic resonance oximetry applications in the brain.

Intravenous recombinant tissue-type plasminogen activator (r-tPA, alteplase) remains the recommended therapy for acute ischemic stroke. However, several factors are limiting its practical use. It makes it urgent for us to search more efficient strategies that can save the ischemic neurons, and safely extend the time window, while in the mean time reducing the detrimental effects for stroke thrombolysis. Hyperbaric oxygen therapy (HBOT) is considered to be potentially neuroprotective. Co-administration of r-tPA and HBOT has already been proved to be effective, safe and feasible in myocardial infarction. In this article, we would like to review whether HBOT has any beneficial effects on r-tPA thrombolysis. If there is, what is the underlying possible mechanisms and how to optimize for maximal effects?