Ischemic cardiac injury can be substantially alleviated by exposing the heart to pharmacological agents such as volatile anesthetics before occurrence of ischemia-reperfusion. A hallmark of this preconditioning phenomenon is its memory, when cardioprotective effects persist even after removal of preconditioning stimulus. Since numerous studies pinpoint mitochondria as crucial players in protective pathways of preconditioning, the aim of this study was to investigate the effects of preconditioning agent isoflurane on the mitochondrial bioenergetic phenotype. Endogenous flavoprotein fluorescence, an indicator of mitochondrial redox state, was elevated to 195 +/- 16% of baseline upon isoflurane application in intact cardiomyocytes, indicating more oxidized state of mitochondria. Isoflurane treatment also elicited partial dissipation of mitochondrial transmembrane potential, which remained depolarized even after anesthetic withdrawal (tetramethylrhodamine fluorescence intensity declined to 83 +/- 3 and 81 +/- 7% of baseline during isoflurane exposure and washout, respectively). Mild uncoupling, with preserved ATP synthesis, was also detected in mitochondria that were isolated from animals that had been previously preconditioned by isoflurane in vivo, revealing its memory nature. These mitochondria, after exposure to hypoxia and reoxygenation, exhibited better preserved respiration and ATP synthesis compared with mitochondria from nonpreconditioned animals. Partial mitochondrial depolarization was paralleled by a diminished Ca(2+) uptake into isoflurane-treated mitochondria, as indicated by the reduced increment in rhod-2 fluorescence when mitochondria were challenged with increased Ca(2+) (180 +/- 24 vs. 258 +/- 14% for the control). In conclusion, isoflurane preconditioning elicits partial mitochondrial uncoupling and reduces mitochondrial Ca(2+) uptake. These effects are likely to reduce the extent of the mitochondrial damage after the hypoxic stress.

Background Signal transduction cascade of anesthetic-induced preconditioning has been extensively studied, yet many aspects of it remain unsolved. Here we investigated the roles of reactive oxygen species (ROS) and mitochondrial uncoupling in cardiomyocyte preconditioning by 2 modern volatile anesthetics: desflurane and sevoflurane. Methods Adult rat ventricular cardiomyocytes were isolated enzymatically. The preconditioning potency of desflurane and sevoflurane was assessed in cell survival experiments by evaluating myocyte protection from the oxidative stress-induced cell death. ROS production and flavoprotein fluorescence, an indicator of flavoprotein oxidation and mitochondrial uncoupling, were monitored in real-time by confocal microscopy. The functional aspect of enhanced ROS generation by the anesthetics was assessed in cell survival and confocal experiments using the ROS scavenger Trolox. Results Preconditioning of cardiomyocytes with desflurane or sevoflurane significantly decreased oxidative stress-induced cell death. That effect coincided with increased ROS production and increased flavoprotein oxidation detected during acute myocyte exposure to the anesthetics. Desflurane induced significantly greater ROS production and flavoprotein oxidation than sevoflurane. ROS scavenging with Trolox abrogated preconditioning potency of anesthetics and attenuated flavoprotein oxidation. Conclusion Preconditioning with desflurane or sevoflurane protects isolated rat cardiomyocytes from oxidative stress-induced cell death. Scavenging of ROS abolishes the preconditioning effect of both anesthetics and attenuates anesthetic-induced mitochondrial uncoupling, suggesting a crucial role for ROS in anesthetic-induced preconditioning and implying that ROS act upstream of mitochondrial uncoupling. Desflurane exhibits greater effect on stimulation of ROS production and mitochondrial uncoupling than sevoflurane.

Exercise reduces LV contractile deterioration in post-infarction heart failure and alleviates the extent of mitochondrial dysfunction, which is paralleled with preserved complex I activity.

The authors conclude that both sarcolemmal and mitochondrial K(ATP) channels play essential and distinct roles in protection afforded by isoflurane. Sarcolemmal K(ATP) channel seems to act as an effector of preconditioning, whereas mitochondrial K(ATP) channel plays a dual role as a trigger and an effector.

The aim of this study was to assess the effects of successive deep dives on endothelial function of large conduit arteries and plasma pro-oxidant and antioxidant activity. Seven experienced divers performed six dives in six consecutive days using a compressed mixture of oxygen, helium and nitrogen (trimix) with diving depths ranging from 55 to 80 m. Before and after first, third and sixth dive, venous gas emboli formation and brachial artery function (flow-mediated dilation, FMD) was assessed by ultrasound. In addition, plasma antioxidant capacity (AOC) was measured by ferric reducing antioxidant power, and the level of oxidative stress was assessed by thiobarbituric acid-reactive substances (TBARS) method. Although the FMD was reduced to a similar extent after each dive, the comparison of predive FMD showed a reduction from 8.6% recorded before the first dive to 6.3% before the third (P = 0.03) and 5.7% before the sixth dive (P = 0.003). A gradual shift in baseline was also detected with TBARS assay, with malondialdehyde values increasing from 0.10 ± 0.02 μmol l⁻¹ before the first dive to 0.16 ± 0.03 before the sixth (P = 0.005). Predive plasma AOC values also showed a decreasing trend from 0.67 ± 0.20 mmol l⁻¹ trolox equivalents (first day) to 0.56 ± 0.12 (sixth day), although statistical significance was not reached (P = 0.08). This is the first documentation of acute endothelial dysfunction in the large conduit arteries occurring after successive deep trimix dives. Both endothelial function and plasma pro-oxidant and antioxidant activity did not return to baseline during the course of repetitive dives, indicating possible cumulative and longer lasting detrimental effects.

Pharmacological preconditioning with volatile anesthetics, or anesthetic-induced preconditioning (APC), is a phenomenon whereby a brief exposure to volatile anesthetic agents protects the heart from the potentially fatal consequences of a subsequent prolonged period of myocardial ischemia and reperfusion. Although not completely elucidated, the cellular and molecular mechanisms of APC appear to mimic those of ischemic preconditioning, the most powerful endogenous cardioprotective mechanism. This article reviews recently accumulated evidence underscoring the importance of mitochondria, reactive oxygen species, and K(ATP) channels in cardioprotective signaling by volatile anesthetics. Moreover, the article addresses current concepts and controversies regarding the specific roles of the mitochondrial and the sarcolemmal K(ATP) channels in APC.

Chronic heart failure is a common complication in patients with type 2 diabetes mellitus (T2DM). T2DM is associated with disturbed metabolism of fat, which can result in excessive accumulation of lipids in cardiac muscle. In the current study, we assessed mitochondrial oxidation of carbohydrates and fatty acids, lipid accumulation, endoplasmic reticulum (ER) stress, and apoptosis in diabetic left ventricle. Left ventricular myocardium from 37 patients (a group of patients with diabetes and a group of patients without diabetes [ejection fraction >50%]) undergoing coronary artery bypass graft surgery was obtained by subepicardial needle biopsy. The group with diabetes had a significantly decreased rate of mitochondrial respiration fueled by palmitoyl-carnitine that correlated with blood glucose dysregulation, while there was no difference in oxidation of pyruvate. Diabetic myocardium also had significantly decreased activity of hydroxyacyl-CoA dehydrogenase (HADHA) and accumulated more lipid droplets and ceramide. Also, markers of ER stress response (GRP78 and CHOP) and apoptosis (cleaved caspase-3) were elevated in diabetic myocardium. These results show that, even in the absence of contractile failure, diabetic heart exhibits a decreased mitochondrial capacity for β-oxidation, increased accumulation of intracellular lipids, ER stress, and greater degree of apoptosis. Lower efficiency of mitochondrial fatty acid oxidation may represent a potential target in combating negative effects of diabetes on the heart.

SCUBA diving is regularly associated with asymptomatic changes in cardiac, pulmonary and vascular function. The aim of this study was to evaluate the changes in vascular/endothelial function following SCUBA diving and to assess the potential difference between two breathing gases: air and nitrox 36 (36% oxygen and 64% nitrogen). Ten divers performed two 3-day diving series (no-decompression dive to 18 m with 47 min bottom time with air and nitrox, respectively), with 2 weeks pause in between. Arterial/endothelial function was assessed using SphygmoCor and flow-mediated dilation measurements, and concentration of nitrite before and after diving was determined in venous blood. Production of nitrogen bubbles post-dive was assessed by ultrasonic determination of venous gas bubble grade. Significantly higher bubbling was found after all air dives as compared to nitrox dives. Pulse wave velocity increased slightly (~6%), significantly after both air and nitrox diving, indicating an increase in arterial stiffness. However, augmentation index became significantly more negative after diving indicating smaller wave reflection. There was a trend for post-dive reduction of FMD after air dives; however, only nitrox diving significantly reduced FMD. No significant differences in blood nitrite before and after the dives were found. We found that nitrox diving affects systemic/vascular function more profoundly than air diving by reducing FMD response, most likely due to higher oxygen load. Both air and nitrox dives increased arterial stiffness, but decreased wave reflection suggesting a decrease in peripheral resistance due to exercise during diving. These effects of nitrox and air diving were not followed by changes in plasma nitrite.