Attenuation of conduction delay by ischemic preconditioning reduces ischemia-induced ventricular arrhythmias

Ischemic preconditioning has been acknowledged as a powerful method of decreasing ischemic injury. However, the antiarrhythmic mechanism of ischemic preconditioning during ischemia is unclear. We studied the effects of ischemic preconditioning on arrhythmias and cardiac electrophysiology during ischemia in Langendorff rat hearts (n = 44). In the non-preconditioned group (PC(-); n = 24), the hearts underwent 5-min zero-flow global ischemia without any prior ischemic preconditioning. In the preconditioned group (PC(+); n = 20), the hearts were preconditioned by three cycles of 3-min zero-flow global ischemia and 5-min reperfusion before undergoing 5-min global ischemia. Ischemic preconditioning reduced the incidence of ischemia-induced arrhythmias (PC(-); 38.9%, PC(+): 8.3%, p < 0.05), shortened monophasic action potential duration (MAPD, P < 0.05), attenuated conduction delay (conduction time; PC(-): 234.2%, PC(+): 173.4%, P < 0.05) and increased the ventricular fibrillation threshold. Although the shortening of MAPD in PC(-) hearts was not influenced by the presence or absence of arrhythmias, conduction time prolongation at 3-min was more obvious in PC(-) hearts with arrhythmia than in PC(-) hearts without arrhythmia (PC(-) with arrhythmia: 220.2%, PC(-) without arrhythmia: 190.7%, P < 0.05). We concluded that ischemic preconditioning could protect the rat hearts from ischemia-induced arrhythmias and postulated that attenuation of conduction delay during ischemia might be an important factor in the antiarrhythmic action of ischemic preconditioning.     

Zacopride缺血后适应抑制大鼠缺血/再灌注性心律失常

目的:探讨心肌内向整流钾通道(K_(ir))激动剂zacopride缺血后适应对大鼠缺血/再灌注性心律失常的影响及可能的电生理学机制。方法:SD大鼠Langendorff离体灌流心脏和在体麻醉大鼠冠状动脉左前降支结扎15 min后松扎15 min诱发缺血/再灌注性心律失常。在冠状动脉左前降支松扎前3 min给予zacopride,观察缺血后适应对再灌注性心律失常的影响。胶原酶法分离大鼠单个心室肌细胞,应用全细胞膜片钳技术观察zacopride对心室肌细胞缺氧/复氧致延迟后除极的影响和对细胞膜表面ATP敏感性钾通道(KATP)的影响。结果:大鼠离体心脏再灌注时预先给予0.1~10μmol/L zacopride可有效抑制再灌注性心律失常的发生。其中0.1μmol/L zacopride为最大效应浓度,可使期前收缩数减少,室速和室颤发生率均下降,持续时间均缩短;再灌前3 min将1μmol/L BaCl_2和0.1μmol/L zacopride同时灌流心脏,BaCl_2可部分逆转zacopride的保护效应(P0.01),表明zacopride的后适应保护与其增强K_(ir)电流的作用有关。在1.5~5μg/kg剂量范围内,zacopride对大鼠在体再灌注诱发的室速和室颤有明显抑制效应,但对期前收缩数无明显影响。1.5μg/kg zacopride抗心律失常的效应与阳性对照药利多卡因(7.5 mg/kg)相似。进一步研究发现zacopride可有效抑制缺氧/复氧所致心室肌细胞延迟后除极,降低其发生率(P0.01)。Zacopride的上述效应与K_(ATP)无关。结论:Zacopride对大鼠缺血/再灌注性心律失常的抑制作用是由激活心肌细胞K_(ir)介导的。激活K_(ir)并消除延迟后除极所诱发的触发性活动可能是zacopride缺血后适应的主要机制。     

Involvement of Ca(2+) in antiarrhythmic effect of ischemic preconditioning in isolated rat heart

We investigated the relationship between the effects of ischemic preconditioning (IPC) and Ca(2+) preconditioning (CPC) on reperfusion-induced arrhythmias. In the control group (noPC), Langendorff-perfused rat hearts were subjected to 5-min zero-flow global ischemia (I) followed by 15-min reperfusion (I/R). In ischemic preconditioning groups (IPC), the hearts were subjected to three cycles of 3-min global ischemia and 5-min reperfusion. In the CPC group, the hearts were exposed to three cycles of 3-min perfusion of higher Ca(2+) (2.3 mmol/l Ca(2+)) followed by 5-min perfusion of normal 1.3 mmol/l Ca(2+), and the hearts were then subjected to I/R. Verapamil was administered in several hearts of the IPC group (VR+IPC). Ventricular arrhythmias upon reperfusion were less frequently seen in the IPC and CPC groups than in the noPC and VR+IPC groups. IPC and CPC could attenuate conduction delay and enhance shortening of the monophasic action potential duration during ischemia. The ventricular fibrillation threshold measured at 1-min reperfusion was significantly higher in the IPC and CPC groups than in the noPC and VR+IPC groups. Verapamil completely abolished the salutary effects of IPC. These results demonstrate that Ca(2+) plays an important role in the antiarrhythmic effect of IPC during reperfusion.     

Antiarrhythmic Activity of Phytoadaptogens in Short-Term Ischemia-Reperfusion of the Heart and Postinfarction Cardiosclerosis

A course of treatment (16 mg/kg orally during 5 days) by Aralia mandshurica or Rhodiola rosea extracts reduced the incidence of ischemic and reperfusion ventricular arrhythmias during 10-min ischemia and 10-min reperfusion. Extracts of Eleutherococcus senticosus, Leuzea carthamoides, and Panax ginseng did not change the incidence of ischemic and reperfusion arrhythmias. Chronic treatment by aralia, rhodiola, and eleutherococcus elevated the ventricular fibrillation threshold in rats with postinfarction cardiosclerosis. Ginseng and leuzea did not change this parameter in rats with postinfarction cardiosclerosis. Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 147, No. 3, pp. 303–306, March, 2009     

Anti-arrhythmic effect of diosgenin in reperfusion-induced myocardial injury in a rat model: activation of nitric oxide system and mitochondrial KATP channel

This study was designed to investigate the anti-arrhythmic effect of diosgenin preconditioning in myocardial reperfusion injury in rat, focusing on the involvement of the nitric oxide (NO) system and mitochondrial ATP-dependent potassium (mitoK_ATP) channels in this scenario. After isolation of the hearts of male Wister rats, the study was conducted in an isolated buffer-perfused heart model. Global ischemia (for 30 min) was induced by interruption of the aortic supply, which was followed by 90-min reperfusion. Throughout the experiment, the electrocardiograms of hearts were monitored using three golden surface electrodes connected to a data acquisition system. Arrhythmias were assessed based on the Lambeth convention and were categorized as number, duration and incidence of ventricular tachycardia (VT), ventricular fibrillation (VF), and premature ventricular complexes (PVC), and arrhythmic score. Additionally, lactate dehydrogenase (LDH) levels in coronary effluent were estimated colorimetrically. Diosgenin pre-administration for 20 min before ischemia reduced the LDH release into the coronary effluent, as compared with control hearts (P < 0.05). In addition, the diosgenin-receiving group showed a lower number of PVC, VT and VF, a reduced duration and incidence of VT and VF, and less severe arrhythmia at reperfusion phase, in comparison with controls. Blocking the mitoK_ATP channels using 5-hydroxydecanoate as well as inhibiting the NO system through prior administration of l-NAME significantly reduced the positive effects of diosgenin. Our finding showed that pre-administration of diosgenin could provide cardioprotection through anti-arrhythmic effects against ischemia–reperfusion (I/R) injury in isolated rat hearts. In addition, mitoK_ATP channels and NO system may be the key players in diosgenin-induced cardioprotective mechanisms.     

Endogenous nitric oxide attenuates hypoxic vasoconstriction of small pulmonary arteries and veins in anaesthetized cats

Ischaemic preconditioning has cardioprotective effects. Reactive oxygen species may be possible mediators. The present study investigated whether low doses of exogenous hydrogen peroxide could mimic preconditioning in isolated, Langendorff-perfused rat hearts. Hearts were subjected to two episodes of 3 min global ischaemia and 5 min reperfusion (n = 17), or were given 10 (n=15), 20 (n=10), 30 (n=20), 40 (n=18), 80 (n=17) or 160 μM (n=10) hydrogen peroxide for 10 min, followed by 10 min recovery, before 25 min global ischaemia and 60 min reperfusion, and compared with ischaemic controls of matching perfusion time (n=17 and n=23). Cardiac performance was assessed by heart rate, left ventricular systolic, end-diastolic and developed pressures, and coronary flow. Severe reperfusion arrhythmias occurred frequently in control hearts, and was attenuated by ischaemic preconditioning. All hearts pretreated with 160 μM hydrogen peroxide had severe arrhythmias throughout reperfusion, while these were not seen in any heart perfused with 20 μM hydrogen peroxide (P< 0.01 compared to controls). Ischaemia and reperfusion induced a minor decrease in heart rate, left ventricular systolic and developed pressures, and increased end-diastolic pressure. Ischaemic preconditioning attenuated the decrease of heart rate and the increase of end-diastolic pressure, and increased coronary flow, while hydrogen peroxide did not significantly attenuate these changes. In conclusion, a low dose of exogenous hydrogen peroxide before global ischaemia inhibited severe reperfusion arrhythmias, but had no other protective effects. The present work does not suggest that reactive oxygen species are important mediators of the preconditioning effects on stunning and arrhythmias in the rat heart.     

Cardioprotective Effect of Ischemic Postconditioning on the Model of Isolated Heart

Irreversible cardiomyocyte damage was induced by 45-min global ischemia followed by 30-min reperfusion in Langendorff-perfused isolated rat heart. Cell damage was assessed by the release of creatine phosphokinase into the perfusate. The hearts were subjected to the following postconditioning protocols: 1) three cycles of 10-sec reperfusion and 10-sec ischemia, total cycle time 20 sec; 2) six cycles of 10-sec reperfusion and 10-sec ischemia, total cycle time 20 sec; 3) three sessions of 20-sec reperfusion and 20-sec ischemia, total cycle time 40 sec; 4) 6 cycles of 20-sec reperfusion and 20-sec ischemia, total cycle time 40 sec; 5) 3 cycles of 30-sec reperfusion and 30-sec ischemia, total cycle time 60 sec. It was found that only postconditioning with a total cycle time of 40 sec or 60 sec prevents myocardial reperfusion injury.     

Defibrotide decreases histamine release in a guinea-pig model of myocardial ischemia and reperfusion “in vitro”

It has been shown that defibrotide (DFT), a single stranded polydeoxyribonucleotide obtained from bovine lungs, has significant anti-thrombotic, profibrinolytic properties and stimulates the synthesis of prostacyclin. The present study was designed to evaluate the effects of DFT in the isolated perfused guinea-pig heart submitted to ischemia and reperfusion.The release of histamine and lactate dehydrogenase (LDH) after left anterior descending coronary artery ligation and reopening was measured, and the changes in electrocardiographic parameters and the computer-aided analysis of cardiac mast cell metachromasia were evaluated. DFT (8.4×10^–6 M) significantly decreased both histamine and LDH release during reperfusion but not in the ischemic phase and attenuated ventricular arrhythmias induced by ischemia-reperfusion, leaving the heart rate unchanged. DFT also reduced the loss of mast cell granule metachromasia and calcium overload consequent to ischemia-reperfusion. Indomethacin (10^–6 M) reduced the protective effect of DFT.     

丹参对家兔急性缺血及再灌注心肌易损期和不应期的影响

本文采用程序性电刺激测定家兔心室易损期（VVP）和有效不应期（ERP）,观察了丹参对缺血和再灌注心肌的保护作用。结果表明,急性心肌缺血（AMI）和再灌注时,丹参组动物VVP明显低于对照组（分别P＜0．05及0．01）,ERP有所延长,但仅在再灌时明显大于对照组（P＜0．05）;AMI时的室颤（VF）发生率明显低于对照组（P＜0．01）,上述结果提示丹参可减轻缺血及再灌注损伤所致的心肌电生理改变,从而降低心肌的易损性。     

Albumin decreases hydrogen peroxide and reperfusion injury in isolated rat hearts

Perfusion with human serum albumin decreased myocardial hydrogen peroxide (H₂O₂) levels (as assessed by inactivation of myocardial catalase activities following ammotriazole pretreatment) and increased myocardial ventricular developed pressures (DP), contractility (+dP/dt) but not relaxation rate (-dP/dt) in isolated crystalloid perfused rat hearts subjected to normothermic global ischemia (20 min) and then reperfusion (40 min). Albumin also decreased H₂O₂ concentrations in vitro. The findings support the possibility that albumin may act as a protective O₂ metabolite scavenger in vivo.     

Protective effects of N-(2-mercaptopropionyl)-glycine against ischemia–reperfusion injury in hypertrophied hearts

The beneficial effects of N-(2-mercaptopropionyl)-glycine (MPG) against ischemia–reperfusion injury in normotensive animals have been previously studied. Our objective was to test the action of MPG during ischemia and reperfusion in hearts from spontaneously hypertensive rats (SHR). Isolated hearts from SHR and age-matched normotensive rats Wistar Kyoto (WKY) were subjected to 50-min global ischemia (GI) and 2-hour reperfusion (R). In other hearts MPG 2 mM was administered during 10 min before GI and the first 10 min of R. Infarct size (IS) was assessed by TTC staining technique and expressed as percentage of risk area. Postischemic recovery of myocardial function was assessed. Reduced glutathione (GSH), thiobarbituric acid reactive substances (TBARS) and SOD cytosolic activity — as estimators of oxidative stress and MnSOD cytosolic activity — as an index of (mPTP) opening were determined. In isolated mitochondria H₂O₂-induced mPTP opening was also measured. The treatment with MPG decreased infarct size, preserved GSH levels and decreased SOD and MnSOD cytosolic activities, TBARS concentration, and H₂O₂ induced-mPTP opening in both rat strains. Our results show that in both hypertrophied and normal hearts an attenuation of mPTP opening via reduction of oxidative stress appears to be the predominant mechanism involved in the cardioprotection against reperfusion injury MPG-mediated.     

珠子参总皂甙、三七总皂甙及绞股兰总皂甙对心肌缺血再灌损伤的保护作用

采用Ｌａｎｇｅｎｄｏｒｆｆ离体心脏灌流方法，以停灌３０分钟，再灌注２０分钟制备大鼠心肌缺血再灌损伤模型。三七总皂甙（ＰＮＳ３０ｍｇ／Ｌ）和绞股兰总皂甙（ＧＰ，３０ｍｇ／Ｌ和５０ｍｇ／Ｌ）显著降低不可逆室颤发生率，５０ｍｇ／Ｌ的ＧＰ显著抑制心肌ＬＤＨ释放，ＰＮＳ和ＧＰ显著提高缺血再灌心肌ＳＯＤ活性，ＧＰ明显降低其ＭＤＡ水平，ＰＮＳ明显降低心肌钙含量。在结扎家兔冠状动脉左室支２小时，再灌注３０分钟所造成的心肌缺血再灌损伤模型中，珠子参总皂甙ＰＪＳ，２５０ｍｇ／ｋｇ）和ＰＮＳ（２００ｍｇ／ｋｇ）轻度改善缺血再灌后的左室功能，显著降低再灌后血浆ＬＤＨ和ＣＰＫ水平，明显减轻心肌钙聚积。以上结果表明：ＰＪＳ，ＰＮＳ和ＧＰ对心肌缺血再灌损伤具有保护作用，ＰＪＳ和ＰＮＳ的作用机理可能与拮抗钙有关，ＧＰ的作用机理可能与抗脂质过氧化有关。     

非创伤性预处理在离体心脏抗再灌注损伤中作用机制的探讨

目的:观察非创伤性肢体缺血预处理对大鼠离体再灌注心肌是否有保护作用。方法:实验采用体重(250±30)gSD雄性大鼠25只随机分成3组,在Langendorff装置上对大鼠离体心脏进行灌流。对照组(C,n=8):在灌注全程均用富氧K-H液(充以95%O₂+5%CO₂),在恒压(8.33kPa)、恒温(37℃)条件下灌注;缺氧/复氧组(A,n=8):预灌15min后,灌注心脏先全心缺血缺氧15min,随后15min复氧再灌注(37℃);非创伤性肢体缺血预处理组(N-WIP,n=9):先将大鼠双后肢捆绑5min,松开5min,反复4次后,随后的方法同R组。在相应时点分别测定冠脉流出液和心肌匀浆中超氧化物歧化酶(SOD)活性,Ca²⁺-Mg²⁺-ATP酶活性和丙二醛(MDA)含量,同时记录心肌细胞的单相动作电位(MAP)和心肌收缩张力曲线。结果:非创伤性肢体缺血预处理能使再灌注心律失常发生率显著低于A组;心肌组织中MDA含量显著低于A组,心肌组织中SOD活性显著高于A组,心肌细胞的膜电位、Ca²⁺-Mg²⁺-ATP酶活性及肌张力较稳定。结论:非创伤性肢体缺血预处理对大鼠离体再灌注心肌有明显的保护作用,可能是通过增强心肌的抗氧化能力、稳定心肌Ca²⁺-Mg²⁺-ATP酶活性和膜相结构等途径,提高心肌细胞对再灌注损伤的抵抗力。     

Defibrotide decreases histamine release in a guinea-pig model of myocardial ischemia and reperfusion “in vitro”

It has been shown that defibrotide (DFT), a single stranded polydeoxyribonucleotide obtained from bovine lungs, has significant anti-thrombotic, profibrinolytic properties and stimulates the synthesis of prostacyclin. The present study was designed to evaluate the effects of DFT in the isolated perfused guinea-pig heart submitted to ischemia and reperfusion.

The release of histamine and lactate dehydrogenase (LDH) after left anterior descending coronary artery ligation and reopening was measured, and the changes in electrocardiographic parameters and the computer-aided analysis of cardiac mast cell metachromasia were evaluated. DFT (8.4×10⁻⁶ M) significantly decreased both histamine and LDH release during reperfusion but not in the ischemic phase and attenuated ventricular arrhythmias induced by ischemia-reperfusion, leaving the heart rate unchanged. DFT also reduced the loss of mast cell granule metachromasia and calcium overload consequent to ischemia-reperfusion. Indomethacin (10⁻⁶ M) reduced the protective effect of DFT.

     

Mild exercise training, cardioprotection and stress genes profile

To improve current knowledge of the molecular mechanisms underlying exercise-induced cardioprotection in a rat model of mild exercise training, Sprague–Dawley rats were trained to run on a treadmill up to 55% of their maximal oxygen uptake for 1 h/day, 3 days/week, 14 weeks, with age-matched sedentary controls (n = 20/group). Rats were sacrificed 48 h after the last training session. Despite lack of cardiac hypertrophy, training decreased blood hemoglobin (7.94 ± 0.21 mM vs. 8.78 ± 0.23 mM, mean ± SE, P = 0.01) and increased both plasma malondialdehyde (0.139 ± 0.005 mM vs. 0.085 ± 0.009 mM, P = 0.05) and the activity of Mn-superoxide dismutase (11.6 ± 0.6 vs. 16.5 ± 1.6 mU/μg, P = 0.01), whereas total superoxide dismutase activity was unaffected. When subjected to 30-min ischemia followed by 90-min reperfusion, hearts from trained rats (n = 5) displayed reduced infarct size as compared to controls (37.26 ± 0.92% vs. 49.09 ± 2.11% of risk area, P = 0.04). The biochemical analyses in the myocardium, which included gene expression profiles, real-time PCR, Western blot and determination of enzymatic activity, showed training-induced upregulation of the following mRNAs and/or proteins: growth-arrest and DNA-damage induced 153 (GADD153/CHOP), heme-oxygenase-1 (HO-1), cyclooxygenase-2 (Cox-2), heat-shock protein 70/72 (HSP70/72), whereas heat-shock protein 60 (HSP60) and glucose-regulated protein 75 (GRP75) were decreased. As a whole, these data indicate that mild exercise training activates a second window of myocardial protection against ischemia/reperfusion by upregulating a number of protective genes, thereby warranting further investigation in man. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Role of l-arginine in preventing myocardial and endothelial injury following ischaemia/reperfusion in the rat isolated heart

The protective effect of l -arginine on ischaemia/reperfusion-induced myocardial injury was investigated in the rat isolated Langendorff perfused heart. Six groups of hearts subjected to 30 min global ischaemia and 30 min reperfusion received either vehicle, d -arginine, l -arginine, the nitric oxide (NO)-donor S-Nitroso-N-Acetyl-d, l -Penicillamine (SNAP), the inhibitor of NO formation N^G-nitro-l -arginine (l -NNA), or l -arginine plus l -NNA. The recoveries of left ventricular double product and coronary flow at the end of reperfusion were significantly higher in the l -arginine group (85±5 and 75±6%, respectively) than in the vehicle group (37±6 and 34±5%, respectively, P<0.05). During both the ischaemic and reperfusion periods, left ventricular end diastolic pressure was lower in the l -arginine group than in the vehicle group. Creatine kinase outflow and the area of no-reflow were smaller in the l -arginine treated hearts (P<0.01). There were no differences between vehicle and d -arginine treated groups. l -NNA did not affect recovery per se but abolished the protective actions of l -arginine. SNAP produced the same protective effects as l -arginine. Acetylcholine-induced endothelium-dependent vasodilation was reduced after ischaemia and reperfusion in the vehicle group but not in the l -arginine group. It is concluded that l -arginine reduces ischaemia/reperfusion-induced myocardial and endothelial injury. The results suggest that the beneficial effects of l -arginine are related to preserved synthesis and release of NO.     

Dual effects of tumor necrosis factor alpha on myocardial injury following prolonged hypoperfusion of the heart

Objective: To examine the dose response of TNFα in an ex vivo rat model of myocardial ischemia reperfusion. Methods and Results: Seventy-two rat hearts were mounted on Langendorff apparatus and perfused with oxygenated Krebs-Henseleit solutions. Ischemia was induced by reducing the perfusate flow rate. During reperfusion, incremental doses of recombinant TNFα were infused as a part of perfusate. TNFα was blocked with monoclonal TNFα antibody. Myocardial function was measured by dP/dT and relaxation time (IVRT). Cellular injury was assessed by released myoglobin and tissue concentration of malondialdehyde activity of the heart homogenates. Baseline +dP/dT was 1645?±?125?mmHg/sec, –dP/dT was 945?±?73?mmHg/sec and IVRT was 65?±?5?msec. At the conclusion of reperfusion period, lower doses of TNFα increased +dP/dT and lowered IVRT. In contrast, the higher doses of TNFα decreased +dP/dT and prolonged IVRT. Pretreating the hearts with monoclonal TNFα antibody completely abolished the effects of TNFα on myocardial contractility and relaxation comparable to ischemia controls. Conclusion: Low dose TNFα improved myocardial function and decreased resultant cellular injury while high dose TNFα decreased myocardial function and increased myocardial injury following ischemia and reperfusion.     

热休克对大鼠再灌注性心律失常作用机制的研究

目的:研究热休克预处理对SD大鼠再灌注性心律失常的作用机制。方法:取55只SD大鼠,随机分为热休克组(H组,n=29)和对照组(C组,n=26)。H组大鼠给予热休克预处理而C组则否。取H组和C组各16只大鼠行Langendorff离体心脏灌注及模拟缺血再灌注。心电图记录复灌时心律失常情况。并检测复灌时心脏流出液肌酸激酶(CK)的活性。同时检测两组心脏组织中70kD热休克蛋白(HSP70)的相对含量和抗氧化酶活性。接着对其余13只H组大鼠和10只C组大鼠测定心脏乳头肌动作电位,即测定静息电位、动作电位振幅、0期最大上升速率(Vmax)等电生理指标,再以台氏液复灌,观察心肌动作电位恢复到缺血液灌流前形态的时间。结果:①H组的再灌注性心律失常严重程度明显较C组为轻。②再灌注过程中心肌CK的释放量H组显著少于C组。③H组心脏组织HSP70表达量显著多于C组。④H组抗氧化酶活性明显强于C组,脂质过氧化物少于C组。⑤台氏液灌流时心肌动作电位H组Vmax显著低于C组,提示热休克对心肌的快Na⁺通道有抑制作用。经缺血液灌流10min后,H组的Vmax变化幅度小于C组。以台氏液复灌后,心肌动作电位恢复到缺血液灌流前形态的时间也以H组为短。结论:热休克预处理可以减轻大鼠心肌再灌注性损伤,减少再灌注性心律失常,此作用与心脏组织中HSP70含量的增加和抗氧化酶活性的显著增强有关,同时还可能与热休克对心肌快Na⁺通道的抑制等电生理作用有关。     

Postnatal development in intermittent hypoxia enhances resistance to myocardial ischemia/reperfusion in male rats

To assess the tolerance of rats that developed from birth in intermittent hypoxia (IH) to myocardial ischemia and reperfusion, we set up a reproducible model in our laboratory. IH rats were raised 60 days from birth in a hypobaric chamber at 5000 m for 6 h daily, while controls were in continuous normoxic conditions. At 60 days after birth, the antioxidant capacity of the heart was determined; arterial and venous partial pressures of oxygen were measured at sea level and 5000 m altitude. In addition, isolated hearts of each group were perfused in Langendorff mode and submitted to 30 min global ischemia followed by 30 min reperfusion to compare functional recovery and lactate dehydrogenase release. For the IH rats, recovery of left ventricular developed pressure (DP), the maximum of the positive or negative first derivative of left ventricular pressure with respect to time (±LV dP/dt), end-diastolic pressure (EDP), and pressure-rate product (PRP) were all superior (P<0.05) to those of control rats. The myocardial antioxidant capacity was also significantly increased in the left ventricle of IH rats. Further, at 5000 m altitude the arterio-venous oxygen gradient (Pa–vO₂) was significantly (P<0.01) higher in the IH rats than in the controls. These data indicate that IH from birth enhances the tolerance of the heart to ischemia/reperfusion, elevates the myocardial antioxidant capacity, and increases oxygen extraction.