Ing and postconditioning alone and whether there is a synergistic effect of both. Rats were subjected to 25 min of coronary artery occlusion followed by 120 min of reperfusion. Infarct size was determined by triphenyltetrazolium staining. The following protocols were used: 1) preconditioning (S-Pre, n = 10, achieved by 2 periods of 5 min sevoflurane administration (1 MAC) followed by 10 min of washout); 2) sevoflurane postconditioning (1 MAC of sevoflurane given for 2 min at the beginning of reperfusion; S-Post, n = 10); 3) administration before and after ischemia (S-Pre + S-Post, n = 10). Protocols 1–3 were repeated in the presence of 5-hydroxydecanoate (5HD), a specific mKATP-channel-blocker (S-Pre + S-Post + 5HD, S-Pre + 5HD: n = 10; S-Post + 5HD: n = 9). Nine rats served as untreated controls (CON) or received 5HD alone (5HD, n = 10). Both S-Pre (23% ± 13% of the area at risk, mean ± sd) and S-Post (18% ± 5%) reduced infarct size compared with CON (49% ± 11%, both P < 0.05). S-Pre + S-Post resulted in a larger reduction of infarct size (12% ± 5%, P = 0.054 versus S-Pre) compared with administration before or after ischemia alone. 5HD diminished the protection in all three sevoflurane treated groups (S-Pre + 5HD, 35% ± 12%; S-Post + 5HD, 44% ± 12%; S-Pre + S-Post + 5HD, 46% ± 14%;) but given alone had no effect on infarct size (41% ± 13%). Sevoflurane preconditioning and postconditioning protects against myocardial ischemia-reperfusion injury. The combination of preconditioning and postconditioning provides additive cardioprotection and is mediated, at least in part, by mKATP-channels....

Background: Exercise promotes metabolic remodeling in the heart, which is associated with physiological cardiac growth; however, it is not known whether or how physical activity–induced changes in cardiac metabolism cause myocardial remodeling. In this study, we tested whether exercise-mediated changes in cardiomyocyte glucose metabolism are important for physiological cardiac growth. Methods: We used radiometric, immunologic, metabolomic, and biochemical assays to measure changes in myocardial glucose metabolism in mice subjected to acute and chronic treadmill exercise. To assess the relevance of changes in glycolytic activity, we determined how cardiac-specific expression of mutant forms of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase affect cardiac structure, function, metabolism, and gene programs relevant to cardiac remodeling. Metabolomic and transcriptomic screenings were used to identify metabolic pathways and gene sets regulated by glycolytic activity in the heart. Results: Exercise acutely decreased glucose utilization via glycolysis by modulating circulating substrates and reducing phosphofructokinase activity; however, in the recovered state following exercise adaptation, there was an increase in myocardial phosphofructokinase activity and glycolysis. In mice, cardiac-specific expression of a kinase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase transgene (Glyco ^Lo mice) lowered glycolytic rate and regulated the expression of genes known to promote cardiac growth. Hearts of Glyco ^Lo mice had larger myocytes, enhanced cardiac function, and higher capillary-to-myocyte ratios. Expression of phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase in the heart (Glyco ^Hi mice) increased glucose utilization and promoted a more pathological form of hypertrophy devoid of transcriptional activation of the physiological cardiac growth program. Modulation of phosphofructokinase activity was sufficient to regulate the glucose–fatty acid cycle in the heart; however, metabolic inflexibility caused by invariantly low or high phosphofructokinase activity caused modest mitochondrial damage. Transcriptomic analyses showed that glycolysis regulates the expression of key genes involved in cardiac metabolism and remodeling. Conclusions: Exercise-induced decreases in glycolytic activity stimulate physiological cardiac remodeling, and metabolic flexibility is important for maintaining mitochondrial health in the heart.

It is known that volatile anaesthetics protect myocardial tissue against ischaemic and reperfusion injury in vitro. In this investigation, we have determined the effects of the inhalation anaesthetics, enflurane, isoflurane, sevoflurane and desflurane, administered only during early reperfusion, on myocardial reperfusion injury in vivo. Fifty chloralose-anaesthetized rabbits were subjected to 30 min of occlusion of a major coronary artery followed by 120 min of reperfusion. Left ventricular pressure (LVP, tip-manometer), cardiac output (CO, ultrasonic flow probe) and infarct size (triphenyltetrazolium staining) were determined. During the first 15 min of reperfusion, five groups of 10 rabbits each received 1 MAC of enflurane (enflurane group), isoflurane (isoflurane group), sevoflurane (sevoflurane group) or desflurane (desflurane group), and 10 rabbits served as untreated controls (control group). Haemodynamic baseline values were similar between groups (mean LVP 106 (SEM 2) mm Hg; CO 281(7) ml min-1). During coronary occlusion, LVP and CO were reduced to the same extent in all groups (LVP 89% of baseline; CO 89%). Administration of inhalation anaesthetics during early reperfusion further reduced both variables, but they recovered after discontinuation of the anaesthetics to values not different from control animals. Infarct size was reduced from 49 (5)% of the area at risk in the control group to 32 (3)% in the desflurane group (P = 0.021), and to 36 (2)% in the sevoflurane group (P = 0.097). In the enflurane group, infarct size was 39 (5)% (P = 0.272). Isoflurane had no effect on infarct size (48 (5)%, P = 1.000). The results show that desflurane and sevoflurane markedly reduced infarct size and therefore can protect myocardium against reperfusion injury in vivo. Enflurane had only a marginal effect and isoflurane offered no protection against reperfusion injury in vivo. These different effects suggest different protective mechanisms at the cellular level.

Volatile anaesthetics protect the heart against reperfusion injury. We investigated whether the cardioprotection induced by sevoflurane against myocardial reperfusion injury was concentration‐dependent. Fifty‐eight α‐chloralose anaesthetized rats were subjected to 25 min of coronary artery occlusion followed by 90 min of reperfusion. Sevoflurane was administered for the first 15 min of reperfusion at concentrations corresponding to 0.75 (n=11), 1.0 (n=11), 1.5 (n=13), or 2.0 MAC (n=12). Eleven rats served as untreated controls. Left ventricular peak systolic pressure (LVPSP, tipmanometer) and cardiac output (CO, flowprobe) was measured. Infarct size (IS, triphenyltetrazolium staining) was determined as percentage of the area at risk. Baseline LVPSP was 131 (126–135) mm Hg (mean (95% confidence interval)) and CO 33 (31–36) ml min^–1, similar in all groups. During early reperfusion, sevoflurane reduced LVPSP in a concentration‐dependent manner to 78 (67–89)% of baseline at 0.75 MAC (not significant vs controls 99 (86–112)%), 71 (62–80)% at 1 MAC (P<0.05), 66 (49–83)% at 1.5 MAC (P<0.05) and 56 (47–65)% at 2 MAC (P<0.05). CO remained constant. While 0.75 MAC of sevoflurane had no effect on IS (34 (27–41)% of the area at risk) compared with controls (38 (31–45)%, P=0.83), 1.0 MAC reduced IS markedly to 23 (17–30)% (P<0.05). Increasing the concentration to 1.5 MAC (23 (17–30)%) and 2 MAC (23 (13–32)%, both P<0.05 vs controls) had no additional protective effect. One MAC sevoflurane protected against myocardial reperfusion injury. Increasing the sevoflurane concentration above 1 MAC resulted in no further protection. Br J Anaesth 2001; 87: 905–11

Background— Inducible nitric oxide synthase (iNOS) is an obligatory mediator of the late phase of ischemic preconditioning, but the mechanisms of its cardioprotective actions are unknown. In addition, it remains unclear whether sustained elevation of iNOS in myocytes provides chronic protection against ischemia/reperfusion injury. Methods and Results— Constitutive overexpression of iNOS in transgenic mice (α-myosin heavy chain promoter) did not induce contractile dysfunction and did not affect mitochondrial respiration or biogenesis, but it profoundly decreased infarct size in mice subjected to 30 minutes of coronary occlusion and 24 hours of reperfusion. In comparison with wild-type hearts, isolated iNOS-transgenic hearts subjected to ischemia for 30 minutes followed by 40 minutes of reperfusion displayed better contractile recovery, smaller infarct size, and less mitochondrial entrapment of 2-deoxy-[ ³ H]-glucose. Reperfusion-induced loss of NAD ⁺ and mitochondrial release of cytochrome c were attenuated in iNOS-transgenic hearts, indicating reduced mitochondrial permeability transition. The NO donor NOC-22 prevented permeability transition in isolated mitochondria, and mitochondrial permeability transition–induced NAD ⁺ loss was decreased in wild-type but not iNOS-null mice treated with the NO donor diethylene triamine/NO 24 hours before ischemia and reperfusion ex vivo. iNOS-mediated cardioprotection was not abolished by atractyloside. Reperfusion-induced production of oxygen-derived free radicals (measured by electron paramagnetic resonance spectroscopy) was attenuated in iNOS-transgenic hearts and was increased in wild-type hearts treated with the mitochondrial permeability transition inhibitor cyclosporin A. Conclusions— Cardiomyocyte-restricted expression of iNOS provides sustained cardioprotection. This cardioprotection is associated with a decrease in reperfusion-induced oxygen radicals and inhibition of mitochondrial swelling and permeability transition.