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Skin ischemic necrosis due to vasospasm and/or insufficient vascularity is the most common complication in the distal portion of the skin flap in reconstructive surgery. This project was designed to test our hypothesis that preoperative subdermal injection of adenoviral vectors encoding genes for vascular endothelial growth factor-165 (Ad.VEGF-165) or endothelial nitric oxide (NO) synthase (Ad.eNOS) effectively augments skin viability in skin flap surgery and that the mechanism of Ad.VEGF-165 gene therapy involves an increase in synthesis/release of the angiogenic and vasodilator factor NO. PBS (0.5 ml) or PBS containing Ad.VEGF-165, Ad.eNOS, or adenovirus (Ad.Null) was injected subdermally into the distal half of a mapped rat dorsal skin flap (4 x 10 cm) 7 days preoperatively, and skin flap viability was assessed 7 days postoperatively. Local subdermal gene therapy with 2 x 10(7)-2 x 10(10) plaque-forming units of VEGF-165 increased skin flap viability compared with PBS- or Ad.Null-injected control (P < 0.05). Subdermal Ad.VEGF-165 and Ad.eNOS gene therapies were equally effective in increasing skin flap viability at 5 x 10(8) plaque-forming units. Subdermal Ad.VEGF-165 therapy was associated with upregulation of eNOS protein expression, Ca2+ -dependent NOS activity, synthesis/release of NO, and increase in capillary density and blood flow in the distal portion of the skin flap. Injection of the NOS inhibitor Nomega-nitro-L-arginine (15 mg/kg im), but not the cyclooxygenase inhibitor indomethacin (5 mg/kg im), 45 min preoperatively completely abolished the increase in skin flap blood flow and viability induced by Ad.VEGF-165 injected subdermally into the mapped skin flap 7 days preoperatively. We have demonstrated for the first time that 1) Ad.VEGF-165 and Ad.eNOS mapped skin flap injected subdermally into the mapped skin flap 7 days preoperatively are equally effective in augmenting viability in the rat dorsal skin flap compared with control, 2) the mechanism of subdermal Ad.VEGF-165 gene therapy in augmenting skin flap viability involves an increase in NO synthesis/release downstream of upregulation of eNOS protein expression and Ca2+ -dependent NOS activity, and 3) the vasodilating effect of NO may predominantly mediate subdermal Ad.VEGF gene therapy in augmenting skin flap blood flow and viability.

We used adenosine A1 receptor agonist N6-1(phenyl-2R-isopropyl)-adenosine (PIA), A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), and ATP-sensitive K+ (KATP) channel blockers sodium 5-hydroxydecanoate (5-HD) and glibenclamide (Glib), as probes to investigate the role and mechanism of adenosine in ischemic preconditioning (IPC) of noncontractile skeletal muscle against infarction, using the pig latissimus dorsi muscle flap model. Except for Glib, all drugs were delivered to each muscle flap by 10-min local intra-arterial infusion to avoid systemic effects. Muscle flaps that were subjected to 4 h of global ischemia and 48 h of reperfusion sustained 40 +/- 2% infarction. IPC with three cycles of 10 min ischemia and reperfusion, preischemic adenosine, or PIA treatment reduced (P < 0.05) muscle infarction to 24 +/- 2, 18 +/- 2, and 24 +/- 2%, respectively. The anti-infarction effect of IPC and adenosine was blocked by DPCPX, 5-HD, and Glib (P < 0.05). Preischemic adenosine treatment also maintained higher muscle contents of phosphocreatine, ATP, and energy charge potential and lower muscle contents of dephosphorylated metabolites and lactate during ischemia and a lower muscle myeloperoxidase (MPO) activity during reperfusion compared with the control (P < 0.05). Preischemic adenosine treatment did not increase muscle content of adenosine during ischemia or reperfusion. Furthermore, adenosine given at the onset of reperfusion was not effective in attenuating muscle MPO activity or infarction. Taken together, these observations indicate that adenosine, through A1 receptors, initiates the mechanism of IPC with postreceptor involvement of KATP channels in skeletal muscle. However, adenosine is unlikely to play a key role in the effector mechanism. Presently, the cause and role of energy sparing and neutrophil inhibitory effects associated with the anti-infarction effect of preischemic adenosine treatment are unknown.

Objective: The aims were to investigate the efficacy of acute ischaemic preconditioning for protection of skeletal muscles against infarction and its effect on muscle blood flow and ischaemic muscle metabolism., Methods: The efficacy of preconditioning was tested by subjecting pig latissimus dorsi and gracilis muscles to different numbers and durations of ischaemia/reperfusion cycles before 4 h of global ischaemia. Infarction was assessed at 48 h of reperfusion, using nitroblue tetrazolium dye. Blood flow in the latissimus dorsi was measured at the end of preconditioning and 1.5 and 3.0 h of reperfusion, using the radioactive microsphere (15 microns) technique. Muscle biopsies were taken from the latissimus dorsi before ischaemia, at the end of 2 and 4 h of ischaemia, and 1.5 h of reperfusion., Results: At least three cycles of 10 min ischaemia and 10 min reperfusion were required for preconditioning of latissimus dorsi and gracilis muscles for protection against infarction. Preconditioning reduced the total infarct size by 44% and 62% in latissimus dorsi and gracilis muscles, respectively. Preconditioning did not affect preischaemia muscle blood flow but it reduced the muscle content (preischaemia reserve) of phosphocreatine and ATP and the muscle energy charge potential (ECP) by 13.5%*, 27.5%*, and 8%* (*P < 0.05), respectively. In spite of a lower preischaemia reserve of phosphocreatine and ATP, the muscle contents of phosphocreatine and ATP and muscle ECP were maintained higher and the lactate lower (*P < or = 0.05) in the preconditioned than in the non-preconditioned (control) muscles at the end of 4 h of ischaemia [phosphocreatine 8.0(SEM 0.4) v 3.2(0.3)*; ATP 9.8(0.7) v 7.8(0.3); ECP 0.72(0.02) v 0.66(0.01)*; lactate 115.4(8.6) v 160.5(11.8)* mumol.g-1 dry muscle]. The level of ATP and ECP also remained significantly higher and the level of lactate significantly lower in the preconditioned than in the non-preconditioned latissimus dorsi muscles at 1.5 h of reperfusion. Hyperaemia was seen in the preconditioned latissimus dorsi muscles at 1.5 h of reperfusion and it subsided by the end of 3h of reperfusion., Conclusions: The protective effect of preconditioning can be induced in pig skeletal muscle but at a higher threshold than reported previously in pig cardiac muscle (one cycle). Preconditioning of pig skeletal muscle is associated with a lower energy metabolism during sustained ischaemia. At the present time, it is not known if this energy sparing effect is a major mechanism of ischaemic preconditioning against infarction in skeletal muscles.

The phenomenon of ischemic preconditioning for augmentation of ischemic tolerance has been well documented in the myocardium of common laboratory animals and human cardiomyocytes. The cellular mechanism of ischemic preconditioning is unclear, but adenosine is most likely the mediator in the rabbit, dog, pig and human. We have demonstrated recently that the protective effect of ischemic preconditioning and adenosine against ischemic injury can also be induced in pig skeletal muscles [116]. We speculate that adenosine is a potential treatment modality for prevention of skeletal muscle ischemic injury in vascular and musculoskeletal reconstructive surgery and in muscle and limb procurement for transplantation in the future. It is hoped that this review will stimulate workers at other laboratories to join the adventure in exploring the cellular mechanism and clinical application of adenosine for augmentation of skeletal muscle ischemic tolerance.

The objectives of the present experiments were to study the effects of long-term low-dose nicotine treatment on skin hemodynamics, viability, and microvascular morphology in 4 x 10 cm dorsally based acute random-pattern skin flaps in the rat. In addition, the reversibility of the nicotine-induced detrimental effects on skin-flap viability following cessation of nicotine treatment also was investigated. Low-dose nicotine (0.6 mg/kg) administered twice daily and subcutaneously for 24 weeks significantly (p less than 0.05) decreased skin-flap capillary blood flow, distal perfusion, and length and area of skin viability compared with the saline-treated control (n = 15). However, these same parameters in rats (n = 15) whose nicotine treatment had been withheld for 2 weeks prior to skin-flap surgery were not significantly different from the control, thus indicating that the detrimental effects of this long-term, low-dose nicotine treatment were reversible. The mean plasma level of nicotine in the nicotine-treated rats was 8.1 +/- 0.4 micrograms/dl and was within the range of plasma nicotine levels reported for human heavy cigarette smokers. Light and electron microscopic studies did not show evidence of histologic damage to the cutaneous microvasculature in acute random-pattern skin flaps and samples of normal (nonoperated) skin in nicotine-treated rats. It is concluded that long-term plasma levels of nicotine similar to those of heavy cigarette smokers are detrimental to the capillary blood flow and viability of random-pattern skin flaps in the rat. These deleterious effects can be avoided if skin flaps are raised 2 weeks after cessation of nicotine treatment. This low-dose nicotine treatment does not cause histologic damage to the microvasculature. Other pathogenic mechanisms of nicotine-induced skin flap ischemia are discussed.

Clinically, ischemic necrosis is one of the most common complications in skin flap surgery, but the etiology is still unclear. The objective of the present experiments was to study the important role of the locally released noradrenaline in the pathogenesis of ischemic necrosis in acute and delayed random pattern skin flaps (4 x 10 cm) raised on both flanks of the pig. In Experiment 1, it was observed that 93, 96, and 94% of the skin contents of noradrenaline were depleted in skin flaps delayed for 2, 4, and 14 days, respectively, compared to the acute skin flaps (n = 8) raised in the same pig. Although the maximum depletion of noradrenaline in the delayed flaps occurred within 2 days of delay, significant (P less than 0.001) increase in the length of dye penetration in the delayed skin flaps was seen after 2 days of delay, compared to the acute skin flaps (n = 12). In Experiments 2 and 3, 5 days of intravenous phenoxybenzamine treatment, starting 2 days preoperatively and at the doses of 0.25, 0.5, 1.0, or 1.5 mg/kg/day, did not have any significant effect on the skin blood flow (n = 24) or viability (1 mg/kg/day; n = 32) in the acute skin flaps compared with the saline-treated control. Similarly, 5 days of intravenous phentolamine treatment (5 mg/kg/day) also did not have any significant effect on the skin blood flow (n = 24) or viability (n = 32) of acute skin flaps compared with the control.(ABSTRACT TRUNCATED AT 250 WORDS)

The importance of the research in skin flap pharmacology is two-fold. First, observations made from the vasoactive drug actions in the vasculature of skin flaps can provide insight into the regulatory mechanism of cutaneous circulation and the pathophysiology of ischemic necrosis in skin flap surgery. Second, there is the possibility that the aforementioned information may eventually contribute to the development of a drug treatment for the augmentation of skin blood flow and viability in acute skin flaps (i.e., to mimic the surgical delay mechanism). To this end, the objectives of this article are: (1) to present a brief review of the recent research progress in the pharmacological treatment of ischemic skin necrosis in experimental flap surgery, and (2) to attempt to identify the future directions and important areas of research to be pursued in the pharmacology of skin flaps.

Background: Flap necrosis remains a major complication in reconstructive surgery. The authors evaluated whether systemic activated protein C, a natural serum anticoagulant with anti-inflammatory, proangiogenic, and cytoprotective properties, can improve ischemic skin flap survival., Methods: Cranially based dorsal cutaneous flaps were elevated on 44 rats. Animals received intravenous injections of activated protein C (25 microg/kg) or saline. Rats were divided into three groups depending on the timing of the first injection: postoperative (45 minutes postoperatively, n = 12), late preoperative (45 minutes preoperatively, n = 5), and early preoperative (3 hours preoperatively, n = 5). In all groups, second and third injections were performed at 3 and 24 hours postoperatively. Flap survival was measured on day 7. Histological and real-time polymerase chain reaction specimens were collected on days 2 and 7 and at 3 and 24 hours, respectively., Results: Postoperative activated protein C improved flap survival (68.9 +/- 4.3 percent) compared with control treatment (39.3 +/- 1.5 percent; p < 0.001). Late preoperative treatment produced diffuse flap hemorrhage. Early preoperative activated protein C injection produced near-complete flap survival (96.1 +/- 1.1 percent for activated protein C versus 50.1 +/- 3.3 percent for control; p < 0.001). Significantly fewer inflammatory cells, improved muscle viability, and increased blood vessel density were observed in activated protein C-treated versus control rats. Activated protein C treatment significantly reduced mRNA levels of intercellular adhesion molecule-1 and tumor necrosis factor-alpha, while increasing levels of Egr-1, vascular endothelial growth factor receptor 2, and Bcl-2., Conclusions: Systemic activated protein C modulates genes involved in angiogenesis, inflammation and apoptosis and improves ischemic flap survival.

Background: In microvascular head and neck reconstruction, ischemia of the free flap tissue is inevitable during microsurgical anastomosis and may affect microvascular free flap perfusion, which is a prerequisite for flap viability and a parameter commonly used for flap monitoring. The aim of this study was to investigate the influence of the number of ischemia intervals and ischemia duration on flap perfusion. Methods: Intraoperative and postoperative flap blood flow, hemoglobin concentration, and hemoglobin oxygen saturation at 2 and 8 mm tissue depths, as measured with the O2C tissue oxygen analysis system, were retrospectively analyzed for 330 patients who underwent microvascular head and neck reconstruction between 2011 and 2020. Perfusion values were compared between patients without (control patients) and with a second ischemia interval (early or late) and examined with regard to ischemia duration. Results: Intraoperative and postoperative flap blood flow at 8 mm tissue depth were lower in patients with early second ischemia intervals than in control patients [102.0 arbitrary units (AU) vs 122.0 AU, P =.030; 107.0 AU vs 128.0 AU, P =.023]. Both differences persisted in multivariable analysis. Intraoperative and postoperative flap blood flow at 8 mm tissue depth correlated weakly negatively with ischemia duration in control patients (r = −.145, P =.020; r = −.124, P =.048). Both associations did not persist in multivariable analysis. Conclusions: The observed decrease in microvascular flap blood flow after early second ischemia intervals may reflect ischemia-related vascular flap tissue damage and should be considered as a confounding variable in flap perfusion monitoring. [ABSTRACT FROM AUTHOR]

Background: The study aimed to evaluate the effects of ischemia used during the rest periods between successive sets on maximal number of performed repetitions, time under tension and bar velocity during the bench press exercise. Methods and materials: Thirteen healthy resistance trained men volunteered for the study (age = 28.5 ± 7.1 years; body mass = 87.2 ± 8.6 kg; bench press 1RM = 143.1 ± 20.7 kg; training experience = 11.0 ± 6.9 years). In experimental protocol the subjects performed 5 sets of bench press exercise at 70%1RM with maximal number of repetitions in each and with 5 minutes rest periods between each set. During the ischemia condition occlusion with 80% arterial occlusion pressure (AOP) was applied using a 10 cm wide cuff, before the first set of the bench press exercise and during all rest periods between sets (for 4.5 minute). During the control condition no ischemia was applied. Results: The two-way repeated measures ANOVA showed a statistically significant interaction effect for time under tension (p = 0.022; η2 = 0.20). However, the results did not show a statistically significant interaction effect for peak bar velocity (p = 0.28; η2 = 0.10) mean bar velocity (p = 0.38; η2 = 0.08), and for number of performed repetitions (p = 0.28; η2 = 0.09). The post hoc analysis for interaction showed significantly shorter time under tension for ischemia condition compared to control in set 1 (p < 0.01). The post hoc analysis for main effect of condition revealed that time under tension was significantly shorter for ischemia compared to control condition (p = 0.04). Conclusion: The results of this study indicate that ischemia intra-conditioning does not increase strength-endurance performance as well as bar velocity during bench press exercise performed to muscle failure. [ABSTRACT FROM AUTHOR]

Introduction: Ischemic preconditioning (IPC) may enhance endurance performance. No previous study has directly compared distinct IPC protocols for optimal benefit. Purpose: To determine whether a specific IPC protocol (ie, number of cycles, amount of muscle tissue, and local vs remote occlusion) elicits greater performance outcomes. Methods: Twelve cyclists performed 5 different IPC protocols 30 min before a blinded 375-kJ cycling time trial (TT) in a laboratory. Responses to traditional IPC (4 x 5-min legs) were compared with those to 8 x 5-min legs and sham (dose cycles), 4 x 5-min unilateral legs (dose tissue), and 4 x 5-min arms (remote). Rating of perceived exertion and blood lactate were recorded at each 25% TT completion. Power (W), heart rate (beats/min), and oxygen uptake (...) (mL ⋅ kg-1 ⋅ min-1) were measured continuously throughout TTs. Magnitude-based-inference statistics were employed to compare variable differences to the minimal practically important difference. Results: Traditional IPC was associated with a 17-s (0, 34) faster TT time than sham. Applying more dose cycles (8 x 5 min) had no impact on performance. Traditional IPC was associated with likely trivial higher blood lactate and possibly beneficial lower ... responses vs sham. Unilateral IPC was associated with 18-s (-11, 48) slower performance than bilateral (dose tissue). TT times after remote and local IPC were not different (0 [-16, 16] s). Conclusion: The traditional 4 x 5-min (local or remote) IPC stimulus resulted in the fastest TT time compared with sham; there was no benefit of applying a greater number of cycles or employing unilateral IPC. [ABSTRACT FROM AUTHOR]

Background and Objective: Acute ischemic preconditioning improves exercise performance. This study was done to determine the effect of four weeks of ischemic preconditioning on vascular grow factor (VEGF), lactate metabolism and fatigue indices. Methods: In this clinical trial study, twenty inactive young men were randomly divided experimental (n=10) and control (n=10) groups. Subjects in experimental group perceived ischemic preconditioning (consisted of four 5-minute cycles of ischemia, followed by five minutes of reperfusion) for four weeks prior training. Blood samples were taken in the rest in order to measuring of VEGF. 48 hours prior and after the last intervention session, subjects performed an anaerobic Wingate test and rating the perceived exertion immediately and blood lactate were measured before, immediately, 5, 10 and 15 min after of Wingate test. Results: 4-week IPC treatment significantly increased VEGF in compared to control group (138.2±8.2 vs 160.1±10.3) (P<0.05). Rating of perceived exertion (6.4±0.5 vs 6±0.1) and lactate accumulation in 15 min after exercise was significantly lower in experimental group in compare to controls (4.1±0.8 vs 5.6±1.2) (P<0.05). There was no significant difference between groups for power output (745.2±131.6 vs 769.7±148.6) and fatigue index (50.58±7.2 vs 46.2±11.8). Conclusion: Four weeks of ischemic preconditioning increase VEGF and reduce rating the perceived exertion and blood lactate after intensive exercise in inactive young men. [ABSTRACT FROM AUTHOR]

Purpose: Although ischaemic preconditioning (IPC), induced by cycles of transient limb ischaemia and reperfusion, seems to improve exercise performance, the optimal duration of ischaemia-reperfusion cycles is not established. The present study investigated the effect of ischaemia-reperfusion duration within each IPC cycle on performance in a 2000-m rowing ergometer test.Methods: After incremental and familiarization tests, 16 trained rowers (mean ± SD: age, 24 ± 11 years; weight, 74.1 ± 5.9 kg; [Formula: see text] peak, 67.2 ± 7.4 mL·kg-1·min-1) were randomly submitted to a 2000-m rowing test preceded by intermittent bilateral cuff inflation of the lower limbs with three cycles of ischaemia-reperfusion, lasting 5 min (IPC-5) or 10 min (IPC-10) at 220 or 20 mmHg (control). Power output, [Formula: see text], heart rate, blood lactate concentration, pH, ratings of perceived exertion (RPE), and near-infrared spectroscopy-derived measurements of the vastus lateralis muscle were continuously recorded.Results: No differences among treatments were found in the 2000-m test (control: 424 ± 17; IPC-5: 425 ± 16; IPC-10: 424 ± 17 s; P = 0.772). IPC-10 reduced the tissue saturation index and oxy-haemoglobin concentration during exercise compared with control. The power output during the last 100-m segment was significantly lower with IPC-10. The IPC treatments increased the heart rate over the first 500 m and decreased the pH after exercise. No alterations were observed in [Formula: see text], blood lactate, or RPE among the trials.Conclusion: In conclusion, IPC does not improve the 2000-m rowing ergometer performance of trained athletes regardless of the length of ischaemia-reperfusion cycles. [ABSTRACT FROM AUTHOR]

This pilot study aimed to evaluate the differential effects of a remote ischemic preconditioning (rIPC) manoeuvre on performance and red blood cell (RBC) deformability compared to a sham control and a placebo setting. Ten male subjects performed three test settings in a single-blind, crossover, and randomized control design. All settings started with 20 min of rest and were followed by 4 cycles of occlusion/reperfusion consisting of 5 min each. During rIPC and placebo, the cuff pressure was inflated to 200 mmHg and 120 mmHg, respectively. During the sham control setting, 10 mmHg pressure was applied. All tests were followed by a cycle exercise with lactate diagnostics. Power at 2 and 4 mmol/l lactate thresholds were calculated. RBC deformability was measured before and after the respective manoeuvre. Results showed that no effect resulted from any manoeuvre on performance values or RBC deformability. But 6 subjects showed a higher power at the 2 mmol/l threshold, and 5 subjects exerted higher power at the 4 mmol/l threshold when the rIPC manoeuvre preceded the exercise. In these responsive subjects, RBC deformability also improved. Hence, rIPC effects are much influenced by the subjects' responsiveness, and improved RBC deformability might contribute to enhanced performance in responsive subjects. [ABSTRACT FROM AUTHOR]

Chronic remote ischemic conditioning (RIC), particularly long-term repeated RIC, has been applied in clinical trials with the expectation that it could play its protective roles for protracted periods. In sports medicine, chronic RIC has also been demonstrated to improve exercise performance, akin to improvements seen with regular exercise training. Therefore, chronic RIC may mimic regular exercise, and they may have similar underlying mechanisms. In this study, we explored the common underlying mechanisms of chronic RIC and physical exercise in protecting multiple organs and benefiting various populations, the advantages of chronic RIC, and the challenges for its popularization. Intriguingly, several underlying mechanisms of RIC and exercise have been shown to overlap. These include the production of many autacoids, enhanced ability for antioxidant activity, modulating immune and inflammatory responses. Therefore, it appears that chronic RIC, just like regular exercise, has beneficial effects in unhealthy, sub-healthy and healthy individuals. Compared with regular exercise, chronic RIC has several advantages, which may provide novel insights into the area of exercise and health. Chronic RIC may enrich the modes of exercise, and benefit individuals with severe diseases. Also, the disabled, and sub-healthy individuals are likely to benefit from chronic RIC either as an alternative to exercise or an adjunct to pharmacological or non-pharmacological therapy. [ABSTRACT FROM AUTHOR]

Fatigue is a phenomenon in which force reduction has been linked to impairment of several biochemical processes. In skeletal muscle, the ATP-sensitive potassium channels (K) are actively involved in myoprotection against metabolic stress. They are present in sarcolemma and mitochondria (mitoK channels). K channel openers like nicorandil has been recognized for their ability to protect skeletal muscle from ischemia-reperfusion injury, however, the effects of nicorandil on fatigue in slow skeletal muscle fibers has not been explored, being the aim of this study. Nicorandil (10 μM), improved the muscle function reversing fatigue as increased post-fatigue tension in the peak and total tension significantly with respect to the fatigued condition. However, this beneficial effect was prevented by the mitoK channel blocker 5-hydroxydecanoate (5-HD, 500 μM) and by the free radical scavenger N-2-mercaptopropionyl glycine (MPG, 1 mM), but not by the nitric oxide (NO) synthase inhibitor Nω-nitro-L-arginine methyl ester (L-NAME, 100 μM). Nicorandil also decreased lipid peroxidation and maintained both reduced glutathione (GSH) levels and an elevated GSH/GSSG ratio, whereas total glutathione (TGSH) remained unaltered during post-fatigue tension. In addition, NO production, measured through nitrite concentrations was significantly increased with nicorandil during post-fatigue tension; this increase remained unaltered in the presence of nicorandil plus L-NAME, nonetheless, this effect was reversed with nicorandil plus MPG. Hence, these results suggest that nicorandil improves the muscle function reversing fatigue in slow skeletal muscle fibers of chicken through its effects not only as a mitoK channel opener but also as NO donor and as an antioxidant. [ABSTRACT FROM AUTHOR]

Purpose: Many of the potential performance-enhancing properties of ischemic preconditioning suggest that the oxygen cost for a given endurance exercise workload will be reduced, thereby improving the economy of locomotion. The aim of this study was to identify whether ischemic preconditioning improves exercise economy in recreational runners.Methods: A randomized sham-controlled crossover study was employed in which 18 adults (age 27 ± 7 years; BMI 24.6 ± 3 kg/m2) completed two, incremental submaximal (65-85% VO2max) treadmill running protocols (3 × 5 min stages from 7.2-14.5 km/h) coupled with indirect calorimetry to assess running economy following ischemic preconditioning (3 × 5 min bilateral upper thigh ischemia) and sham control. Running economy was expressed as mlO2/kg/km and as the energy in kilocalories required to cover 1 km of horizontal distance (kcal/kg/km).Results: Ischemic preconditioning did not influence steady-state heart rate, oxygen consumption, minute ventilation, respiratory exchange ratio, energy expenditure, and blood lactate. Likewise, running economy was similar (P = 0.647) between the sham (from 201.6 ± 17.7 to 204.0 ± 16.1 mlO2/kg/km) and ischemic preconditioning trials (from 202.8 ± 16.2 to 203.1 ± 15.6 mlO2/kg/km). There was no influence (P = 0.21) of ischemic preconditioning on running economy expressed as the caloric unit cost (from 0.96 ± 0.12 to 1.01 ± 0.11 kcal/kg/km) compared with sham (from 1.00 ± 0.10 to 1.00 ± 0.08 kcal/kg/km).Conclusions: The properties of ischemic preconditioning thought to affect exercise performance at vigorous to severe exercise intensities, which generate more extensive physiological challenge, are ineffective at submaximal workloads and, therefore, do not change running economy. [ABSTRACT FROM AUTHOR]

Ischemic preconditioning ( IPC) of one or two limbs improves performance of exercise that recruits the same limb(s). However, it is unclear whether IPC application to another limb than that in exercise is also effective and which mechanisms are involved. We investigated the effect of remote IPC ( RIPC) on muscle fatigue, time to task failure, forearm hemodynamics, and deoxygenation during handgrip exercise. Thirteen men underwent RIPC in the lower limbs or a control intervention ( CON), in random order, and then performed a constant load rhythmic handgrip protocol until task failure. Rates of contraction and relaxation (ΔForce/ΔTime) were used as indices of fatigue. Brachial artery blood flow and conductance, besides forearm microvascular deoxygenation, were assessed during exercise. RIPC attenuated the slowing of contraction and relaxation throughout exercise ( P < 0.05 vs CON) and increased time to task failure by 11.2% (95% confidence interval: 0.7-21.7%, P <0.05 vs CON). There was no significant difference in blood flow, conductance, and deoxygenation between conditions throughout exercise ( P > 0.05). In conclusion, RIPC applied to the lower limbs delayed the development of fatigue during handgrip exercise, prolonged time to task failure, but was not accompanied by changes in forearm hemodynamics and deoxygenation. [ABSTRACT FROM AUTHOR]

Both surgical delay and ischemic preconditioning (IP) have been shown to be effective in improving the survival of flaps. We used a variety of flap delay methods and IP to increase the surviving area of the transverse rectus abdominis musculocutaneous (TRAM) flap in rats, and the results are compared in between. A 6- x 3-cm-sized TRAM flap in 40 Wistar rats was allocated into five groups. Group 1: TRAM flap was elevated from nondominant pedicle, and the flap was sutured to the original bed. Group 2: Left superior deep epigastric vessels (SDEV) were cut; 1 week later, TRAM flap was elevated. Group 3: Only skin incision was done; 1 week later, TRAM flap was elevated. Group 4: Skin incision was done, and the left SDEV were cut; 1 week later, TRAM flap was elevated. Group 5: TRAM flap was elevated; IP was performed using three cycles of 10 minutes of repeated ischemia/reperfusion (I/R) periods, and the flap was sutured to the original bed. The surviving area of the flap was statistically significant between the control and groups 2,4, and 5 (p < 0.001), and groups 4 and 2 were superior to group 5. Although preconditioning has been intensively studied for the last two decades and partly provided its beneficial effects in I/R injury, we determined the IP increased the surviving area of the TRAM flap but not effective as much as surgical delay method. [ABSTRACT FROM AUTHOR]

Background: It has been shown that estrogens have a protective effect with regard to tissue ischemia. Therefore, in this macroscopic and histological investigation, the effect of estradiol benzoate on skin flap viability was studied in sham-operated and ovariectomized Sprague-Dawley rats. Methods: Three months prior to flap surgery a group of rats underwent ovariectomy, while the remaining animals underwent a sham operation. Subsequently, all rats had a 2 × 8-cm skin flap created on the dorsum. Rats were randomly divided into estradiol- or saline-treated groups. Treatment started either on the day of flap excision or 3 days prior to the surgery. Results: Our results showed that administration of estradiol benzoate prior to and after flap surgery significantly decreases skin flap necrosis in both sham-operated and ovariectomized rats, with the highest survival rate in animals where treatment started 3 days prior to flap surgery. Conclusion: In conclusion, the observed protective effect of estradiol on skin flap viability could potentially be applied to plastic and reconstructive surgery in postmenopausal women. Nevertheless, further research is needed to explain the exact underlying mechanism and to find the optimal treatment protocol for human clinical practice. Level of Evidence I: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors . [ABSTRACT FROM AUTHOR]

This experiment establishes the principles of using the compound muscle action potential (CMAP) as a possible postoperative monitor for free muscle grafts. Twenty rabbits were divided into two groups of ten each to investigate the effects of ischemia on CMAP of the muscles. Rectus femoris model was used and contralateral muscle was used as control. In all muscles total normothermic ischemia of 1.5 hours to mimic the time needed for transfer and inset of the flap was followed by occlusion of the artery in one group and vein in another group after 3 hours. During this ischemia of 1 hour, the CMAP amplitudes decreased and the latencies were prolonged. Latency prolongation was detected within 10 minutes of total, arterial, or venous ischemia. During the revascularization, both amplitude and latency improved, but not to the original values at the start. The results show that CMAP monitoring can provide easily detectable, objective indication of vascular compromise to a muscle graft within as early as 10 minutes of total, arterial, and venous ischemia. Changes in latency are more constant and predictable compared with amplitude changes. This method can provide continuous monitoring and can be used in buried muscle grafts. [ABSTRACT FROM AUTHOR]

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Brief episodes of non-lethal ischemia, commonly known as "ischemic preconditioning" (IP), are protective against cell injury induced by infarction. Moreover, muscle IP has been found capable of improving exercise performance. The aim of the study was the comparison of standard exercise performances carried out in normal conditions with those carried out following IP, achieved by brief muscle ischemia at rest (RIP) and after exercise (EIP). Seventeen physically active, healthy male subjects performed three incremental, randomly assigned maximal exercise tests on a cycle ergometer up to exhaustion. One was the reference (REF) test, whereas the others were performed after the RIP and EIP sessions. Total exercise time (TET), total work (TW), and maximal power output (Wmax), oxygen uptake (VO2max), and pulmonary ventilation (VEmax) were assessed. Furthermore, impedance cardiography was used to measure maximal heart rate (HRmax), stroke volume (SVmax), and cardiac output (COmax). A subgroup of volunteers (n = 10) performed all-out tests to assess their anaerobic capacity. We found that both RIP and EIP protocols increased in a similar fashion TET, TW, Wmax, VEmax, and HRmax with respect to the REF test. In particular, Wmax increased by ~4% in both preconditioning procedures. However, preconditioning sessions failed to increase traditionally measured variables such as VO2max, SVmax, COmax, and anaerobic capacity. It was concluded that muscle IP improves performance without any difference between RIP and EIP procedures. The mechanism of this effect could be related to changes in fatigue perception. [ABSTRACT FROM AUTHOR]

The effects of piracetam on flap survival, ischemia-reperfusion (I/R) injury, and vascular endothelial growth factor (VEGF) expression were evaluated in this study. Unipedicled epigastric flap model was used in 36 rats and was evaluated within 4 groups. The flap was elevated and untreated in Group 1. Postoperative piracetam treatment was given for 7 days in Group 2. In Group 3, 4 hours of ischemia and 2 hours of reperfusion were applied. I/R was applied to Group 4 and piracetam was given 30 minutes before reperfusion and postoperatively for 7 days. Laser Doppler flowmetry was used to measure blood flow changes. VEGF expression was determined using immunohistochemical methods on tissue samples taken after the completion of 2 hours reperfusion in groups 3 and 4. Flap necrosis was measured on the day 7 in all groups. Blood flow rates did not show significant difference between piracetam treated and untreated I/R groups. Piracetam significantly reduced necrosis area both in ischemic and nonischemic flaps (p<0.05). VEGF expression was significantly increased in piracetam-treated Group 4 compared with Group 3 (p = 0.005). This experimental study demonstrates that systemic piracetam treatment improves survival of pedicled flaps, reduces necrosis amounts, and increases VEGF expression in I/R induced flaps. [ABSTRACT FROM AUTHOR]

Repeated episodes of ischemia followed by reperfusion, commonly referred to as ischemic preconditioning (IPC), represent an endogenous protective mechanism that delays cell injury. IPC also increases blood flow and improves endothelial function. We hypothesize that IPC will improve physical exercise performance and maximal oxygen consumption. The purpose of the study was to examine the effect of ischemic preconditioning in leg skeletal muscles on cycling exercise performance in healthy individuals. Fifteen healthy, well-trained subjects performed two incremental maximal exercise tests on a bicycle ergometer. Power output, oxygen consumption, ventilation, respiratory quotient, and heart rate were measured continuously. Blood pressure and blood lactate were measured before and after the test. One exercise test was performed after the application of ischemic preconditioning, using a protocol of three series of 5-min ischemia at both legs with resting periods of 5 min in between. The other maximal cycling test served as a control. Tests were conducted in counterbalanced order, at least 1 week apart, at the same time of the day. The repeated ischemic periods significantly increased maximal oxygen consumption from 56.8 to 58.4 ml/min per kg (P = 0.003). Maximal power output increased significantly from 366 to 372 W (P = 0.05). Ischemic preconditioning had no effect on ventilation, respiratory quotient, maximal heart rate, blood pressure or on blood lactate. Repeated short-term leg ischemia prior to an incremental bicycle exercise test improves maximal oxygen consumption by 3% and power output by 1.6%. This protocol, which is suggested to mimic the effects of ischemic preconditioning, may have important implications for exercise performance. [ABSTRACT FROM AUTHOR]

Ischaemic preconditioning increases the survival of flaps. Random-pattern McFarlane dorsal flaps were raised in 30 female Wistar rats, which were divided into three groups. An ischaemic conditioning protocol with clamping of the pedicle was used. No clamping was used in the control group, and the pedicle was clamped for 15 minutes in the second group and 20 minutes in the third group daily to see if the duration of ischaemia had any effects on the viability of the flaps. The pedicles were divided earlier in the clamped groups than in the control group. The size of necrotic areas of the flaps in the clamped groups was smaller than on the control group. Daily postoperative intermittent ischaemic conditioning in the pedicles of the flaps had a protective effect on their survival and led to earlier division of the pedicles. [ABSTRACT FROM AUTHOR]

The aim of our study was to establish whether ischemic preconditioning (IPC) directly before performing a small bowel anastomosis has an effect on anastomotic stability and healing. Forty male Wistar rats were randomized to five groups: control (CO, n = 8) with preparation of the superior mesenteric artery (SMA) but without IPC. IPC groups had different intervals of ischemia (occlusion of the SMA) and reperfusion: 10 min ischemia and 20 min reperfusion (IPC10/20, n = 7), 10 min ischemia and 30 min reperfusion (IPC10/30, n = 8), 15 min ischemia and 20 min reperfusion (IPC15/20, n = 8), and 15 min ischemia and 30 min reperfusion (IPC15/30, n = 9). On the fourth postoperative day, the animals were relaparotomized: bursting pressure, hydroxyproline concentration, and histological ischemia mucosal injury scale of the anastomosis were assessed. Four days after operation, the mean bursting pressure was 73 ± 6 mmHg in the control group, whereas it was significantly higher in IPC10/20 (113 ± 11 mmHg; p = 0.018), IPC10/30 (110 ± 13 mmHg; p = 0.001), and IPC15/30 (124 ± 9 mmHg; p = 0.003). IPC15/20 did not show a significant difference (63 ± 2 mmHg; p = 0.4). We did not find a significant effect regarding hydroxyproline concentration, but IPC diminished mucosal injury. IPC directly before performing a small bowel anastomosis has a time-dependent beneficial effect on anastomotic stability, thus indicating a new clinical approach to improve the healing process of intestinal anastomosis. [ABSTRACT FROM AUTHOR]

Viability and functional results of a segment replantation depend on the prevention of deleterious effects of ischemia. Prolonged ischemia leads to alterations in the microcirculation: thrombosis, edema, production of oxygen free radicals, and platelet aggregation. The effect of IIb-IIIa glycoprotein inhibitors was tested in a partial limb amputation model submitted to warm ischemia. The male Wistar rats were divided into four groups: G1 with 0 hours of ischemia and saline ( N?=?20), G2 with 6 hours of ischemia and saline ( N?=?24), G3 with 6 hours of ischemia and abciximab ( N?=?23), and G4 with 6 hours of ischemia and tirofiban ( N?=?29). The limbs were observed for 7 days and classified as viable or nonviable. Viability and mortality rates were obtained and analyzed by Q-square and Fisher exact tests ( P?

Hydrogen sulfide (H2S) is one of three endogenous gases, along with carbon monoxide (CO) and nitric oxide (NO), that exert a variety of important vascular actions in vivo. Although it has been demonstrated that CO or NO can trigger the development of a preconditioned phenotype in postischemic tissues, it is unclear whether H2S may also induce protection in organs subsequently exposed to ischemia-reperfusion (I/R). In light of these observations, we postulated that preconditioning with the exogenous H2S donor sodium hydrosulfide (NaHSPC) would inhibit leukocyte rolling (LR) and adhesion (LA) induced by I/R. We used intravital microscopic techniques to demonstrate that NaHS-PC 24 h, but not 1 h, before I/R causes postcapillary venules to shift to an anti-inflammatory phenotype in wild-type (WT) mice such that these vessels fail to support LR and LA during reperfusion. The protective effect of NaHS-PC on LR was largely abolished by coincident pharmacological inhibition of NO synthase (NOS) in WT animals and was absent in endothelial NOS-deficient (eNOS) mice. A similar pattern of response was noted in WT mice treated concomitantly with NaHS plus p38 mitogen-activated protein kinase (MAPK) inhibitors (SB 203580 or SK-86002). Whereas the reduction in LA induced by antecedent NaHS was attenuated by pharmacological inhibition of NOS or p38 MAPK in WT mice, the antiadhesive effect of NaHS was still evident in eNOS-/- mice. Thus NaHS-PC prevents LR and LA by triggering the activation of an eNOS- and p38 MAPK-dependent mechanism. However, the role of eNOS in the anti-adhesive effect of NaHS-PC was less prominent than its effect to reduce LR. [ABSTRACT FROM AUTHOR]

Administration of Na+/H+ exchange isoform-1 (NHE-1) inhibitors before ischemia has been shown to attenuate myocardial infarction in several animal models of ischemia-reperfusion injury. However, controversy still exists as to the efficacy of NHE- 1 inhibitors in protection of myocardial infarction when administered at the onset of reperfusion. Furthermore, the efficacy of NHE-1 inhibition in protection of skeletal muscle from infarction (necrosis) has not been studied. This information has potential clinical applications in prevention or salvage of skeletal muscle from ischemia-reperfusion injury in elective and trauma reconstructive surgery. The objective of this research project is to test our hypothesis that the NHE-1 inhibitor cariporide is effective in protection of skeletal muscle from infarction when administered at the onset of sustained ischemia or reperfusion and to study the mechanism of action of cariporide. In our studies, we observed that intravenous administration of cariporide 10 min before ischemia (1 or 3 mg/kg) or reperfusion (3 mg/kg) significantly reduced infarction in pig latissimus dorsi muscle flaps compared with the control, when these muscle flaps were subjected to 4 h of ischemia and 48 h of reperfusion (P < 0.05; n = 5 pigs/group). Both preischemic and postischemic cariporide treatment (3 mg/kg) induced a significant decrease in muscle myeloperoxidase activity and mitochondrial-free Ca2+ content and a significant increase in muscle ATP content within 2 h of reperfusion (P < 0.05; n = 4 pigs/group). Preischemic and postischemic cariporide treatment (3 mg/kg) also significantly inhibited muscle NHE-1 protein expression within 2 h of reperfusion after 4 h of ischemia, compared with the control (P < 0.05; n = 3 pigs/group). These observations support our hypothesis that cariporide attenuates skeletal muscle infarction when administered at the onset of ischemia or reperfusion, and the mechanism involves attenuation of neutrophil accumulation and mitochondrial-free Ca2+ overload and preservation of ATP synthesis in the early stage of reperfusion. [ABSTRACT FROM AUTHOR]

We tested our hypothesis that postischemic conditioning (PostC) is effective in salvage of ischemic skeletal muscle from reperfusion injury and the mechanism involves inhibition of opening of the mitochondrial permeability transition pore (mPTP). In bilateral 8 × 13 cm pig latissimus dorsi muscle flaps subjected to 4 h ischemia, muscle infarction increased from 22 ± 4 to 41 ± 1% between 2 and 24 h reperfusion and remained unchanged at 48 (38 ± 6%) and 72 (40 ± 1%) h reperfusion (P <0.05; n = 4 pigs). PostC induced by four cycles of 30-s reperfusion/reocclusion at the onset of reperfusion after 4 h ischemia reduced muscle infarction from 44 ± 2 to 22 ± 2% at 48 h reperfusion. This infarct protective effect of PostC was mimicked by intravenous injection of the mPTP opening inhibitor cyclosporin A or NIM-811 (10 mg/kg) at 5 mm before the end of 4 h ischemia and was abolished by intravenous injection of the mPTP opener atractyloside (10 mg/kg) at 5 mm before PostC (P < 0.05; n = 4-5 pigs). PostC or intravenous cyclosporin A injection at s mm before reperfusion caused a decrease in muscle myeloperoxidase activity and mitochondrial free Ca2+ concentration and an increase in muscle ATP content after 4 h ischemia and 2 h reperfusion compared with the time-matched controls. These effects of PostC were abolished by intravenous injection of atractyloside at 5 mm before PostC (P < 0.05; n = 6 pigs). These observations support our hypothesis that PostC is effective in salvage of ischemic skeletal muscle from reperfusion injury and the mechanism involves inhibition of opening of the mPTP. [ABSTRACT FROM AUTHOR]

Free flap necrosis continues to be a significant problem in microvascular surgery. Despite improved microsurgical techniques and equipment, flap loss remains the major operative complication. Although ischemia-induced reperfusion injury remains a significant etiologic factor in flap loss, there is continued interest in endothelial mechanisms that regulate microvascular injury and thrombosis. In recent years, activated protein C (APC) has emerged as a promising therapy in counteracting microcirculatory injury. APC is an anticoagulant that is also involved in signaling pathways that modulate inflammation, apoptosis, and vascular permeability. This article presents the mechanism of action of APC and the benefits of this therapeutic agent, including a possible role in the prevention of free flap ischemia-reperfusion injury. [ABSTRACT FROM AUTHOR]

Although adenosine exerts cardio-and vasculoprotective effects, the roles and signaling mechanisms of different adenosine receptors in mediating skeletal muscle protection are not well understood. We used a mouse hindlimb ischemia-reperfusion model to delineate the function of three adenosine receptor subtypes. Adenosine A3 receptor-selective agonist 2-chloro-N6-(3-iodobenzyl)adenosine-5′-N-methyluronamide (C1-IBMECA; 0.07 mg/kg ip) reduced skeletal muscle injury with a significant decrease in both Evans blue dye staining (5.4 ± 2.6%, n = 8 mice vs. vehicle-treated 28 ± 6%, n = 7 mice, P < 0.05) and serum creatine kinase level (1,840 ± 910 U/1, n = 13 vs. vehicle-treated 12,600 ± 3,300 U/1, n = 14, P < 0.05), an effect that was selectively blocked by an A3 receptor antagonist 3-ethyl-5-benzyl-2-methyl-6-pheny1–4-phenylethynyl- 1 ,4-(± )-dihydropyridine-3,5-dicarboxylate (MRS-1191; 0.05 mg/kg). The adenosine A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA; 0.05 mg/kg) also exerted a cytoprotective effect, which was selectively blocked by the A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 0.2 mg/kg). The adenosine A2A receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5′-N-ethylcarboxamidoadenosine (CGS-21680; 0.07 mg/kg)-induced decrease in skeletal muscle injury was selectively blocked by the A2A antagonist 2-(2-furanyl)-7-[3-(4-methoxyphenyl)propyl]-7H- pyrazolo[4,3-e] [1 ,2,4]triazolo[1,5-C]pyrimidin-5-amine (SCH-442416; 0.017 mg/kg). The protection induced by the A3 receptor was abrogated in phospholipase C-ß2/ß3 null mice, but the protection mediated by the A1 or A2A receptor remained unaffected in these animals. The adenosine A3 receptor is a novel cytoprotective receptor that signals selectively via phospholipase C-ß and represents a new target for ameliorating skeletal muscle injury. [ABSTRACT FROM AUTHOR]

Insufficient perfusion of distal flap areas, which may lead to partial necrosis, still represents a challenge in reconstructive surgery. In the process of microvascular and endothelial dysfunction, endothelins (ETs) and their receptors may play an important role. Therefore, the aim of the study was to investigate in a chronic in vivo model the effect of various ET-receptor antagonists in critically perfused flap tissue. A random pattern musculocutaneous flap was elevated in the back of 25 C57BL/6 mice and fixed into a dorsal skinfold chamber. Repetitive intravital fluorescence microscopy was performed over a 10-day observation period, assessing arteriolar diameter, arteriolar blood flow (aBF), functional capillary density (FCD), the area of tissue necrosis, and the development of newly formed blood vessels. ET-receptor blockers were administrated intraperitoneally 30 min before induction of ischemia, as well as daily during the subsequent 4-day period, including (1) BQ-123, a specific ET-A-receptor antagonist (ET-A = 1 mg/kg), (2) BQ-788, a selective ET-B-receptor antagonist (ET-B = 1 mg/kg), and (3) PD-142893, a nonselective ET-AB-receptor antagonist (ET-AB = 0.5 mg/kg). Animals receiving saline only served as controls ( n = 7). Despite an increase in aBF during the 10-day observation period (day 1 = 1.92 ± 0.29 nl/s; day 10 = 4.70 ± 1.64 nl/s), the flaps of saline-treated controls showed a distinct decrease in FCD (94 ± 12 cm/cm2). This perfusion failure resulted in flap necrosis of 52 ± 3%. Selective blockade of the ET-B receptor caused a further increase in aBF already at day 1 (2.97 ± 0.42 nl/s), which persisted during the following 10-day observation period (day 10 = 5.74 ± 0.69 nl/s). Accordingly, adequate FCD could be maintained (day 10 = 215 ± 8 cm/cm2; p < 0.05 vs control), resulting in a significant reduction in flap necrosis (day 10 = 25 ± 4%; p < 0,05). In contrast, neither selective blockade of the ET-A receptor nor nonselective ET-A- and ET-B-receptor blockade were able to significantly affect aBF when compared to controls (day 1 = ET-A = 1.39 ± 0.10 nl/s; ET-AB = 1.53 ± 0.80 nl/s; n.s.). Accordingly, flap necrosis after ET-A- and ET-AB-receptor inhibition did not differ from that of controls (day 10 = ET-A: 46 ± 10%; ET-AB = 51 ± 7%). Our data show that only selective ET-B-receptor inhibition is capable of maintaining nutritive perfusion and, hence, reducing necrosis in critically perfused flap tissue. Accordingly, administration of ET-B-receptor antagonists may be considered in the treatment of critically perfused flaps. [ABSTRACT FROM AUTHOR]

Remote ischemic preconditioning reduces myocardial infarction (Ml) in animal models. We tested the hypothesis that the systemic protection thus induced is effective when ischemic preconditioning is administered during ischemia (PerC) and before reperfusion and examined the role of the K+-dependent ATP (KATP) channel. Twenty 20-kg pigs were randomized (10 in each group) to 40 min of left anterior descending coronary artery occlusion with 120 min of reperfusion. PerC consisted of four 5-min cycles of lower limb ischemia by tourniquet during left anterior descending coronary artery occlusion. Left ventricular (LV) function was assessed by a conductance catheter and extent of infarction by tetrazolium staining. The extent of MI was significantly reduced by PerC (60.4 ± 14.3 vs. 38.3 ± 15.4%, P = 0.004) and associated with improved functional indexes. The increase in the time constant of diastolic relaxation was significantly attenuated by PerC compared with control in ischemia and reperfusion (P = 0.01 and 0.04, respectively). At 120 min of reperfusion, preload-recruitable stroke work declined 38 ± 6% and 3 ± 5% in control and PerC, respectively (P = 0.001). The force-frequency relation was significantly depressed at 120 min of reperfusion in both groups, but optimal heart rate was significantly lower in the control group (P = 0.04). There were fewer malignant arrhythmias with PerC during reperfusion (P = 0.02). These protective effects of PerC were abolished by glibenclamide. Intermittent limb ischemia during myocardial ischemia reduces MI, preserves global systolic and diastolic function, and protects against arrhythmia during the reperfusion phase through a KATP channel- dependent mechanism. Understanding this process may have important therapeutic implications for a range of ischemia-reperfusion syndromes. [ABSTRACT FROM AUTHOR]

This study reviews the current understanding of ischemic preconditioning (IP) in experimental and clinical setting, and the mechanisms that mediate the complex processes involved as a tool to protect against ischemia and reperfusion (I/R) injury, but is not intended as a complete literature review of preconditioning. IP has been mainly elucidated in cardiac ischemia. Recent reports confirm the efficacy of pre- and postconditioning in cardiac surgery and percutaneous coronary interventions in humans. IP utilizes endogenous as well as distant mechanisms in skeletal muscle, liver, lung, kidney, intestine and brain in animal models to convey varying degrees of protection from I/R injury. Specifically, preconditioned tissues exhibit altered energy metabolism, better electrolyte homeostasis and genetic reorganization, as well as less oxygen-free radicals and activated neutrophils release, reduced apoptosis and better microcirculatory perfusion. To date, there are few human studies, but recent trials suggest that human liver, lung and skeletal muscle acquire protection after IP. Present data address the potential therapeutic application of IP in the prevention of I/R damage specially aimed at clinical transplantation. IP is ubiquitous but more research is required to fully translate these findings to the clinical arena. [ABSTRACT FROM AUTHOR]

Ischemia-reperfusion (I/R) injury causes skeletal muscle infarction and ischemic preconditioning (IPC) augments ischemic tolerance in animal models. To date, this has not been demonstrated in human skeletal muscle. This study aimed to develop an in vitro model to investigate the efficacy of simulated IPC in human skeletal muscle. Human skeletal muscle strips were equilibrated in oxygenated Krebs-Henseleit-HEPES buffer (37°C). Aerobic and reperfusion phases were simulated by normoxic incubation and reoxygenation, respectively. lschemia was simulated by hypoxic incubation. Energy store, cell viability, and cellular injury were assessed using ATP, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MIT), and lactate dehydrogenase (LDH) assays, respectively. Morphological integrity was assessed using electron microscopy. Studies were designed to test stability of the preparation (n = 5–11) under normoxic incubation over 24 h; the effect of I, 2, 3, 4, or 6 h hypoxia followed by 2 h of reoxygenation; and the protective effect of hypoxic preconditioning (HPC; s mm of hypoxia/5 mm of reoxygenation) before 3 h of hypoxia/2 h of reoxygenation. Over 24 h of normoxic incubation, muscle strips remained physiologically intact as assessed by MIT, ATP, and LDH assays. After 3 h of hypoxia/2 h of reoxygenation, MIT reduction levels declined to 50.1 ± 5.5% (P < 0.05). MTT reduction levels in HPC (82.3 ± 10.8%) and normoxic control (81.3 ± 10.2%) groups were similar and higher (P < 0.05) than the 3 h of hypoxia/2 h of reoxygenation group (45.2 ± 5.8%). Ultrastructural morphology was preserved in normoxic and HPC groups but not in the hypoxia/reoxygenation group. This is the first study to characterize a stable in vitro model of human skeletal muscle and to demonstrate a protective effect of HPC in human skeletal muscle against hypoxia/reoxygenation-induced injury. [ABSTRACT FROM AUTHOR]

Inadequate blood perfusion and ischemia–reperfusion (I/R) injury in the surgical skin flap are believed to be the major factors that cause harmful changes within the tissue and vasculature, resulting in flap necrosis. Reactive oxygen radical species (ROS), in part, are believed to play an important role in this injury. Melatonin, in many physiological conditions, has been shown to have direct and indirect antioxidative effects and free-radical-scavenging properties. Therefore, it may have a beneficial effect on I/R-induced flap injury. In this study, the possible protective effects of melatonin were investigated in I/R injury of rat epigastric (axial pattern) flaps. Ischemia was achieved for 12 h by occlusion of inferior epigastric artery. Melatonin or vehicle was administered 1 h before flap elevation and was continued for 6 days after ischemia. I/R injury elevated malondialdehyde (MDA), an end product of lipid peroxidation, and nitric oxide (NO) levels while the glutathione (GSH) content was reduced. Myeloperoxidase (MPO) activity, which is known to be related to tissue neutrophil accumulation, was found to be statistically higher in the I/R group when compared with the sham group. Administration of melatonin significantly decreased MDA, NO and MPO levels and elevated the GSH content. Moreover, melatonin reduced the flap necrosis area, which was determined using a planimetric method. In conclusion, melatonin, a potent scavenger of free radicals, plays a major role in preventing the inferior epigastric arterial I/R-induced flap necrosis, based on planimetric flap survival and biochemical results. The beneficial effects of melatonin in I/R injury implies the involvement of free radicals in flap damage. [ABSTRACT FROM AUTHOR]

We have previously demonstrated that remote ischemic preconditioning (IPC) by instigation of three cycles of 10-min occlusion/reperfusion in a hindlimb of the pig elicits an early phase of infarct protection in local and distant skeletal muscles subjected to 4 h of ischemia immediately after remote IPC. The aim of this project was to test our hypothesis that hindlimb remote IPC also induces a late phase of infarct protection in skeletal muscle and that KATP channels play a pivotal role in the trigger and mediator mechanisms. We observed that pig bilateral latissimus dorsi (LD) muscle flaps sustained 46 ± 2% infarction when subjected to 4 h of ischemi/48 h of reperfusion. The late phase of infarct protection appeared at 24 h and lasted up to 72 h after hindlimb remote IPC. The LD muscle infarction was reduced to 28 ± 3, 26 ± 1, 23 ± 2, 24 ± 2 and 24 ± 4% at 24, 28, 36, 48 and 72 h after remote IPC, respectively (P « 0.05; n = 8). In subsequent studies, hindlimb remote IPC or intravenous injection of the sarcolemmal KATP, (sKATP) channel opener P-1075 (2 μg/kg) at 24 h before 4 h of sustained ischemia (i.e., late preconditioning) reduced muscle infarction from 43 ± 4% (ischemic control) to 24 ± 2 and 19 ± 3%, respectively (P « 0.05, n = 8). Intravenous injection of the sKATP channel inhibitor HMR 1098 (6 mg/kg) or the nonspecific KATP channel inhibitor glibenclamide (Glib; 1 mg/kg) at 10 min before remote IPC completely blocked the infarct-protective effect of remote IPC in LD muscle flaps subjected to 4 h of sustained ischemia at 24 h after remote IPC. Intravenous bolus injection of the mitochonchial KATP (mKATP) channel inhibitor 5-hydroxydecanoate (5-HD; 5 mg/kg) immediately before remote IPC and 30-min intravenous infusion of 5-HD (5 mg/kg) during remote IPC did not affect the infarct-protective effect of remote IPC in LD muscle flaps. However, intravenous Glib or 5-HD, but not HMR 1098, given 24 h after remote IPC completely blocked the late infarct-protective effect of remote IPC in LD muscle flaps. None of these drug treatments affected the infarct size of control LD muscle flaps. The late phase of infarct protection was associated with a higher (P « 0.05) muscle content of ATP at the end of 4 h of ischemia and 1.5 h of reperfusion and a lower (P « 0.05) neutrophilic activity at the end of 1.5 h of reperfusion compared with the time-matched control. In conclusion, these findings support our hypothesis that hindlimb remote IPC induces an uninterrupted long (48 h) late phase of infarct protection, and sKATP and mATP channels play a central role in the trigger and mediator mechanism, respectively. [ABSTRACT FROM AUTHOR]

The article examines an in vivo model of chronic ischemia and necrosis to determine whether local hypothermia was capable of inducing stress proteins such as heat-shock protein (HSP) 70 and haem oxygenase (HO) 1 and effective in improving tissue microcirculation and survival. Microcirculatory dysfunction and tissue necrosis were analyzed quantitatively by means of intravital fluorescence microscopy. HSP-70 and HO-1 protein expression were examined by western blot analysis. HO-1 distribution within the flap tissue was also analyzed by immunohistochemistry. The results of the study were summarized.

Hepatic injury after hepatic stress is caused by several mechanisms, including inflammatory reaction and microcirculatory disturbance. Levels of thromboxane, a vasoconstrictive eicosanoid, have been shown to increase in systemic circulation after different types of hepatic stress such as endotoxemia, hepatic ischemia-reperfusion, hepatectomy, liver transplantation, hemorrhagic shock and resuscitation, hepatic cirrhosis, and alcoholic liver injury. The production of thromboxane from the liver is also enhanced under these stresses, which may act on the liver in an autocrine or a paracrine fashion. Kupffer cells, resident hepatic macrophages, may be a major source of stress-induced thromboxane, although other cell types in the liver such as sinusoidal endothelial cells and hepatocytes may also produce this eicosanoid. Thromboxane induces hepatic damage through vasoconstriction, platelet aggregation, induction of leukocyte adhesion, up-regulation of proinflammatory cytokines, and induction of other vasoconstrictor release. In this regard, administration of cyclooxygenase inhibitor, specific thromboxane synthase inhibitor, and specific thromboxane receptor antagonists has been shown to protect from severe hepatic injury elicited by these hepatic stresses. Furthermore, blockade of Kupffer cell function by administration of gadolinium chloride showed salutary effects in preventing hepatic damage in bile duct ligation models. This review article summarizes the recent knowledge of the role of thromboxane in various types of hepatic stress and the effects of thromboxane inhibitors in these models. [ABSTRACT FROM AUTHOR]

Background: Adenosine receptor stimulation induces several effects that could limit ischemia-reperfusion injury. We hypothesize that treatment with the nucleoside uptake inhibitor dipyridamole increases endogenous adenosine and limits ischemia-reperfusion injury in humans. Methods: Ischemia-reperfusion injury was studied in forearm skeletal muscle by technetium Tc 99m-labeled annexin A5 scintigraphy. Ischemia-reperfusion injury was induced by unilateral forearm ischemic exercise. Immediately on reperfusion, annexin A5 labeled with technetium Tc 99m was administered intravenously, and ischemia-reperfusion injury was expressed as the percentage difference in radioactivity between the experimental arm and the control arm 1 and 4 hours after reperfusion. Targeting was quantified in the region of the thenar muscle and forearm flexor muscles. This approach was used in 9 healthy male volunteers after a 1-week treatment with dipyridamole (200 mg, slow release, twice daily) and in 23 control subjects. Results: Dipyridamole treatment significantly reduced annexin A5 targeting in skeletal muscle compared with the control group (thenar region, 13% ± 7% versus 22% ± 15% at 1 hour after reperfusion and 9% ± 6% versus 27% ± 13% at 4 hours for dipyridamole and control groups, respectively [P = .01]; flexor region, 4% ± 8% versus 7% ± 6% at 1 hour after reperfusion and 1% ± 4% versus 10% ± 9% at 4 hours for dipyridamole and control groups, respectively [P = .01]). Conclusions: One week of oral treatment with the nucleoside uptake inhibitor dipyridamole (200 mg, slow release, twice daily) significantly limits ischemia-reperfusion injury in humans in vivo, as assessed by technetium Tc 99m-labeled annexin A5 scintigraphy of forearm skeletal muscle. [Copyright &y& Elsevier]

Using intravital microscopy in a chronic in vivo mouse model, we studied the demarcation of myocutaneous flaps and evaluated microvascular determinants for tissue survival and necrosis. Chronic ischemia resulted in a transition zone, characterized by a red fringe and a distally adjacent white falx, which defined the demarcation by dividing the proximally normal from the distally necrotic tissue. Tissue survival in the red zone was determined by hyperemia, as indicated by recovery of the transiently reduced functional capillary density, and capillary remodeling, including dilation. hyperperfusion, and increased tortuosity. Angiogenesis and neovascularization were not observed over the 10-day observation period. The white rim distal to the red zone, appearing as ‘falx lunatica,’ showed a progressive decrease of functional capillary density similar to that of the necrotic distal area but without desiccation, and thus transparency, of the tissue. Development of the distinct zones of the critically ischemic tissue could be predicted by partial tissue oxygen tension (PtO2) analysis by the time of flap elevation. The falx lunatica evolved at a PtO2 between 6.2 ± 1.3 and 3.8 ± 0.7 mmHg, whereas tissue necrosis developed at <3.8 ± 0.7 mmHg. Histological analysis within the falx lunatica revealed interstitial edema formation and muscle fiber nuclear rarefaction but an absence of necrosis. We have thus demonstrated that ischemia-induced necrosis does not demarcate sharply from normal tissue but develops beside a fringe of tissue with capillary remodeling an adjacent falx lunatica that survives despite nutritive capillary perfusion failure, probably by direct oxygen diffusion. [ABSTRACT FROM AUTHOR]

We previously demonstrated in the pig that instigation of three cycles of 10 min of occlusion and reperfusion in a hindlimb by tourniquet application (∼300 mmHg) elicited protection against ischemia-reperfusion injury (infarction) in multiple distant skeletal muscles subsequently subjected to 4 h of ischemia and 48 h of reperfusion, but the mechanism was not studied. The aim of this project was to test our hypothesis that mitochondrial ATP-sensitive potassium (KATP) (mKATP) channels play a central role in the trigger and mediator mechanisms of hindlimb remote ischemic preconditioning (IPC) of skeletal muscle against infarction in the pig. We observed in the pig that hindlimb remote IPC reduced the infarct size of latissimus dorsi (LD) muscle flaps (8 × 13 cm) from 45 ± 2% to 22 ± 3% (n = 10; P < 0.05). The nonselective KATP channel inhibitor glibenclamide (0.3 mg/kg) or the selective mKATP channel inhibitor 5-hydroxydecanoate (5-HD, 5 mg/kg), but not the selective sarcolemmal KATP (sKATP) channel inhibitor HMR-1098 (3 mg/kg), abolished the infarct-protective effect of hindlimb remote IPC in LD muscle flaps (n = 10, P < 0.05) when these drugs were injected intravenously at 10 min before remote IPC. In addition, intravenous bolus injection of glibenclamide (1 mg/kg) or 5-HD (10 mg/kg) at the end of hindlimb remote IPC also abolished the infarct protection in LD muscle flaps (n = 10; P < 0.05). Furthermore, intravenous injection of the specific mKATP channel opener BMS-191095 (2 mg/kg) at 10 min before 4 h of ischemia protected the LD muscle flap against infarction to a similar extent as hindlimb remote IPC, and this infarct-protective effect of BMS-191095 was abolished by intravenous bolus injection of 5-HD (5 mg/kg) at 10 min before or after intravenous injection of BMS-191095 (n = 10; P < 0.05). The infarct protective effect of BMS-191095 was associated with a higher muscle content of ATP at the end of 4 h of ischemia and a decrease in muscle neutrophilic myeloperoxidase activity at the end of 1.5 h of reperfusion compared with the time-matched control (n = 10, P < 0.05). These observations led us to conclude that mKATP channels play a central role in the trigger and mediator mechanisms of hindlimb remote IPC of skeletal muscle against infarction in the pig, and the opening of mKATP channels in ischemic skeletal muscle is associated with an ATP-sparing effect during sustained ischemia and attenuation of neutrophil accumulation during reperfusion. [ABSTRACT FROM AUTHOR]

Distal skin ischemic necrosis is a common complication in skin flap surgery. The pathogenesis of skin flap ischemic necrosis is unclear, and there is no clinical treatment available. Here, we used the 4 × 10 cm rat dorsal skin flap model to test our hypothesis that subcutaneous injection of vascular endothelial growth factor 165 (VEGF165) in skin flaps at the time of surgery is effective in augmentation of skin flap viability, which is associated with an increase in nitric oxide (NO) production, and the mechanism involves 1) an increase in skin flap blood flow in the early stage after surgery and 2) enhanced angiogenesis subsequently to sustain increased skin flap blood flow and viability. We observed that subcutaneous injection of VEGF165 in skin flaps at the time of surgery increased skin flap viability in a dosedependant manner. Subcutaneous injection of VEGF165 at the dose of 2 µg/flap increased skin flap viability by 28% (P < 0.05; n = 8). Over 80% of this effect was blocked by intramuscular injection of the NO synthase (NOS) inhibitor Nω-nitro-L-arginine (13 mg/kg) 45 min before surgery (P < 0.05; n = 8). The VEGF165 treatment also increased skin flap blood flow (2.68 ± 0.63 ml·min-1·100 g-1) compared with the control (1.26 ± 0.10 ml·min-1·100 g-1; P < 0.05, n = 6) assessed 6 h postoperatively. There was no change in skin flap capillary density at this time point. VEGF165-induced increase in capillary density (32.2 ± 1.1 capillaries/mm²; P < 0.05, n = 7) compared with control (24.6 ± 1.4 capillaries/mm²) was seen 7 days postoperatively. Them was also evidence to indicate that VEGF165induced NO production in skin flaps was stimulated by activation of NOS activity followed by upregulation of NOS protein expression. These observations support our hypothesis and for the first time provide an important insight into the mechanism of acute local VEGF165 protein therapy in mitigation of skin flap ischemic necrosis. [ABSTRACT FROM AUTHOR]

Noninvasive remote ischemic preconditioning for global protection of skeletal muscle against infarction. Am J Physiol Heart Circ Physiol 285: H1435-H1443, 2003. First published June 5, 2003: 10.1152/ajpheart.00106.2003.—The aim of this study was to investigate the efficacy and mechanism of action of a noninvasive remote ischemic preconditioning (IPC) technique for the protection of multiple distant skeletal muscles against ischemic necrosis (infarction). It was observed in the pig thai three cycles of 10-min occlusion and reperfusion in a hindlimb by tourniquet application reduced the infarction of latissimus dorsi (LD), gracilis (GC), and rectus abdominis (RA) muscle flaps by 55%, 60%, and 55%, respectively, compared with their corresponding control (n = 6, P < 0.01) when they were subsequently subjected to 4 h of ischemia and 48 h of reperfusion. This infarct-protective effect of remote IPC in LD muscle flaps was abolished by an intravenous bolus injection of the nonselective opioid receptor antagonist naloxone (3 mg/kg) 10 min before remote IPC and a continuous intravenous infusion (3 mg/kg) during remote IPC and by an intravenous bolus injection of the selective δ[sub 1]-opioid receptor antagonist 7-benzylidenealtrexene maleate (3 mg/kg). However, this infarct-protective effect of remote IPC was net affected by an intravenous bolus injection of the ganglionic blocker hexamethonium chloride (20 mg/kg) or the nonspecific adenosine receptor antagonist 8-(p-sulfophenyl)theophylline (10 mg/kg) or by a local intra-arterial injection of the adenosine[sub 1] receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (3 mg/muscle flap) given 10 min before remote IPC. It was also observed that this remote IPC of skeletal muscle against infarction was associated with a slower rate of muscle ATP depletion during the 4 h of sustained ischemia and a reduced muscle neutrophilic myeloperoxidase activity after 1.5 h of reperfusion. These observations led us to speculate that noninvasive remote IPC by brief cycles of occlusion and reperfusion in a pig hindlimb is effective in global protection of skeletal muscle against infarction. This infarct-protective effect is most likely triggered by the activation of opioid receptors in the skeletal muscle, and remote IPC is associated with an energy-sparing effect during sustained ischemia and attenuation of neutrophil accumulation during reperfusion. [ABSTRACT FROM AUTHOR]

The phenomenon of ischemic preconditioning, in which a period of sublethal ischemia can profoundly protect the cell from infarction during a subsequent ischemic insult, has been responsible for an enormous amount of research over the last 15 years. Ischemic preconditioning is associated with two forms of protection: a classical form lasting 2 h after the preconditioning ischemia followed a day later by a second window of protection lasting 3 days. Both types of preconditioning share similarities in that the preconditioning ischemia provokes the release of several autacoids that trigger protection by occupying cell surface receptors. Receptor occupancy activates complex signaling cascades which during the lethal ischemia converge on one or more end-effectors to mediate the protection. The end-effectors so far have eluded identification, although a number have been proposed. A range of different pharmacological agents that activate the signaling cascades at the various levels can mimic ischemic preconditioning leading to the hope that specific therapeutic agents can be designed to exploit the profound protection seen with ischemic preconditioning. This review examines, in detail, the complex mechanisms associated with both forms of preconditioning as well as discusses the possibility to exploit this phenomenon in the clinical setting. As our understanding of the mechanisms associated with preconditioning are unravelled, we believe we can look forward to the development of new therapeutic agents with novel mechanisms of action that can supplement current treatment options for patients threatened with acute myocardial infarction. [ABSTRACT FROM AUTHOR]

Ischemic preconditioning refers to the endogenous mechanism of protection against a sustained ischemic insult following an initial, brief ischemic stimulus. Ischemia-reperfusion injury of the liver is a major cause of morbidity and mortality in liver surgery and transplantation and ischemic preconditioning is a promising strategy for improving the outcome of liver surgery. The preconditioning phenomenon was first described in a canine model of myocardial ischemia-reperfusion injury in 1986 and since then has been shown to exist in other organs including skeletal muscle, brain, kidneys, retina and liver. In the liver, the preconditioning effect has been demonstrated in rodents and a recent study has demonstrated human clinical benefits of preconditioning during hemihepatectomies. Ischemic preconditioning has been described as an adaptive response and although the precise mechanism of hepatoprotection from preconditioning is unknown it is likely to be a receptor-mediated process. Several hypotheses have been proposed and this review assesses possible mechanisms of ischemic preconditioning and its role in hepatic surgery and liver transplantation. The future lies in defining the mechanisms of the ischemic preconditioning effect to allow drug targeting to induce the preconditioning response.Copyright © 2003 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Acute tissue ischemia is usually followed by considerable disturbances of cellular metabolism that often lead to cell death. Reperfusion improves cellular function by withdrawing the toxic products of ischemia and providing energy sources, although sometimes it worsens it. The purpose of this experimental work is to study the metabolic disturbances in skeletal muscle tissue of canines after prolonged acute ischemia in relation to the values of certain substances (ATP, lactate, pyruvate, the ratio of lactate to pyruvate [L/P], and glucose) and whether the alterations in the values of these substances could be used as prognostic indices of the magnitude of tissue damage and the possibility of inverting it. We used 15 mongrel dogs. Complete acute ischemia was induced in the right lower limb lasting 12 h. Reperfusion also lasted for 12 h. The left lower limb was used as reference value. Before the beginning of ischemia, at ½, 1, 6, and 12 h after the induction of ischemia, and at ½, 1, 6, and 12 h after the restoration of circulation, blood samples, and tissue biopsies were obtained from the healthy and the experimental limb for the measurement of ATP, lactate, pyruvate, the ratio of L/P, and glucose. From the statistical analysis of the values of the controlled parameters the following were concluded: The changes in ATP, lactate, pyruvate, and the L/P ratio in the venous blood of the experimental limb and in the intracellular space of the suffering skeletal muscle could be used as indices to evaluate ischemic injury to the skeletal muscles, the course of its development, and the possibility of reversal after reperfusion. [ABSTRACT FROM AUTHOR]

Conventional ischemic preconditioning is the phenomenon whereby brief episodes of myocardial ischemia render the ischemic territory resistant to a subsequent, sustained ischemic insult. A growing body of evidence further indicates that brief ischemia applied in distant organs and tissues can also protect naïve, virgin myocardium from ischemic injury. In this review, we describe the initial observations that provided the impetus for the study of ‘remote preconditioning’, and summarize our current knowledge of the three facets of ‘preconditioning at a distance’ – intra-cardiac, inter-organ and transferred inter-cardiac preconditioning. [ABSTRACT FROM AUTHOR]