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.     

Cyclooxygenase products are not involved in the protection against myocardial infarction afforded by preconditioning in rabbit. Cyclooxygenase pathway's involvement in preconditioning.

The mechanism whereby preconditioning with a transient period of ischemia renders the heart resistant to infarction from a subsequent ischemic insult is unknown. The purpose of this study was to determine whether cyclooxygenase pathways are involved in preconditioning's protection. Two inhibitors of that pathway, meclofenamate (MEC) and aspirin (ASP), were test in an in situ and a blood perfused isolated heart model, respectively. Preconditioning was achieved with 5 minute ischemia and 10 minutes reperfusion. All in situ hearts underwent 30 minute ischemia followed by 180 minute reperfusion, while the isolated hearts experienced 45 minute ischemia plus 120 minute reperfusion. Infarct size was measured with TTC stain. In the in situ model, 39.9% +/- 4.2% of the ischemic zone was infarcted in control hearts but only 8.8% +/- 2.2% in preconditioning hearts. Pretreatment with MEC (5 mg/Kg) caused no alteration of infarct size in either non preconditioned (34.3% +/- 8.3%) or preconditioned hearts (6.7% +/- 3.3%). In isolated hearts, 45 minute ischemia caused 31.0% +/- 5.9% of the ischemic zone to be infarcted in control hearts and only 5.4% +/- 2.2% in preconditioned hearts. Pretreatment with ASP (1 mg/Kg) failed to affect infarct size in either non preconditioned (35.7% +/- 3.7%) or preconditioned hearts (10.2% +/- 1.9%). The data indicate that cyclooxygenase pathways are not involved in the preconditioning's protection.     

Brief apnea induces myocardial ischemic tolerance by an opioid-insensitive mechanism.

BACKGROUND: Intermittent brief "preconditioning" (PC) ischemia has been shown to render the heart resistant to a subsequent sustained ischemic insult, in part through an opioid-dependent mechanism. Using the rabbit model, we tested the hypothesis that intermittent in vivo apnea elicits a cardioprotective response similar to that achieved with conventional PC ischemia. In addition, we sought to determine if infarct size reduction seen in this model was stimulated via opioid receptor activation. METHODS: Anesthetized, intubated rabbits (n=35) were randomized to receive three 4.5-min bouts of apnea interspersed with 5 min normal ventilation or time-matched standard ventilation (controls). Upon completion of the in vivo PC/control period, the hearts were excised and assessed for ischemic tolerance on a modified Langendorff apparatus (40 min global ischemia+2h reperfusion). To assess the contribution of opioid receptor stimulation, two additional control and PC groups received the nonspecific opioid antagonist naloxone (10 mg/kg) prior to the in vivo intervention phase. Infarct size (delineated by tetrazoliam staining and expressed as a percentage of the left ventricle [LV]) was compared among the four groups by ANOVA. RESULTS: Infarct size was significantly reduced in hearts that received antecedent apneic PC when compared with controls (63+/-5% vs. 34+/-8%) of the LV, respectively; P<.05). Pretreatment with naloxone had no significant effect on infarct size in nonpreconditioned hearts (80+/-6%) and did not inhibit the protective effects of apnea-induced PC (52+/-10% in naloxone+PC group). CONCLUSIONS: Intermittent apnea evokes significant myocardial ischemic tolerance through an opioid-insensitive mechanism.     

局部缺血"预处理"诱导家兔相邻非缺血心肌热休克蛋白70基因表达

目的：研究兔心局部缺血“预处理”后,局部缺血和相邻非缺血心肌热休克蛋白７０（ＨＳＰ７０）ｍＲＮＡ的水平变化。方法：提取心肌组织总ＲＮＡ,用ＨＳＰ７０探针进行斑点杂交。结果：缺血预处理组的缺血区和非缺血区ＨＳＰ７０ｍＲＮＡ表达水平均显著高于对照组相应部位（Ｐ＜００５）,而每组内的缺血区及非缺血区间无显著差异（Ｐ＞００５）。结论：局部缺血“预处理”后,缺血和非缺血区两处心肌的内反应呈“一致性”;缺血预处理对心肌的保护作用可能与ＨＳＰ７０的合成增多有关。     

Preconditioning in intact and previously diseased myocardium: laboratory or clinical dilemma?

We studied the effects of various cycles of preconditioning (PC) (one cycle, 1 x PC; two cycles, 2 x PC; three cycles, 3 x PC; and four cycles, 4 x PC) on cardiac function, infarct size, and the incidence of reperfusion-induced arrhythmias in isolated hearts obtained from rabbits with hypercholesterolemia. After 8 weeks of hypercholesterolemia, hearts were subjected to 30 min of ischemia followed by 120 min of reperfusion. Various cycles of PC resulted in a "cycle-dependent" reduction in infarct size in the age-matched nonhypercholesterolemic group. In the 8-week hypercholesterolemic group, increasing cycles of PC resulted in a significant increase in infarct size from their nonpreconditioned ischemic/reperfused control value of 44 +/- 5% to 45 +/- 6%, 49 +/- 5%, 59 +/- 6% (p < 0.05), and 58 +/- 5% (p < 0.05), respectively. PC increased the vulnerability of the myocardium to reperfusion-induced arrhythmias in hypercholesterolemics indicating that PC may be an "intact heart" phenomenon. The effects of PC appear currently to be a dilemma in laboratories and clinics. The solution to the problem of PC in intact and diseased myocardium requires further data from two different sources: (a) previously "diseased" animals, and (b) diseased human myocardium from clinics. Once these data are available, then the effects under which PC will be beneficial rather than harmful could be established and the dilemma solved.     

Changes in catecholamine, angiotensin converting enzyme and adenosine triphosphatase in ischemic preconditioning rat hearts

Changes in catecholamine ,angiotensin converting enzy me and adenosine triphosphatase in ischemic preconditioning rat hearts     

缺血预处理的抗心律失常作用

应用离体大鼠心脏Ｌａｎｇｅｎｄｏｒｆｆ灌流全心缺血模型，研究缺血预处理的抗收律失常作用及其作用的持续时间。发现ＩＰ可降低自搏心脏和人工起搏心脏的心率失常发生及严重程度，并引起心室颤动阈的升高；ＩＰ对随后的缺血－再灌过程中室性频率的改变无改善作用。     

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。     

Pretreatment with tyrosine kinase inhibitor attenuates the reduction of apoptosis 24 h after ischemic preconditioning

We investigated whether ischemic preconditioning (PC) attenuates ischemia/reperfusion-induced injury in part by decreasing apoptosis and whether tyrosine kinase (TK) can regulate the signaling pathway leading to apoptosis in delayed cardioprotection. Six groups of rabbits were studied in the early phase (EP) and in the delayed phase (DP): (1) sham-operated control animals were received vehicle only (Veh-sham); (2) rabbits that received I.V. genistein (a nonspecific TK inhibitor) 10 min before ischemia (Gen-sham); (3) rabbits that received I.V. daidzein (an inactive structural analog of genistein) 10 min before ischemia (Dzn-sham); (4) rabbits preconditioned with 4 cycles of 5-min occlusion of left anterior descending coronary artery (LAD) and 10-min reperfusion (PC); (5) rabbits that received I.V. genistein, 10 min before PC (Gen-PC); (6) rabbits that received I.V. daidzein 10 min before PC (Dzn-PC). All rabbits underwent 30-min ischemia followed by 180-min reperfusion. Infarct size in the PC, Gen-PC, and Dzn-PC groups in the EP was significantly (p < 0.0001) reduced relative to controls Gen and Dzn. Delayed cardioprotection was blocked significantly (p < 0.0001) by genistein. In the EP, apoptosis was significantly (p < 0.0001) decreased in PC, Gen-PC, and Dzn-PC groups relative to controls Gen and Dzn. In the DP, a reduction of apoptosis was not seen in the Gen-PC group. This study suggests that PC reduces ischemic injury in part by decreasing apoptosis after ischemia/reperfusion and also that TK phosphorylation is involved in the signal transduction cascade leading to the decline of apoptosis in the DP.     

Ischemic preconditioning triggers nuclear translocation of thioredoxin and its interaction with Ref-1 potentiating a survival signal through the PI-3-kinase-Akt pathway

Thioredoxin (Trx-1), a key mediator of cellular redox homeostasis and cell survival, is implicated in redox signaling in the ischemic myocardium. To investigate further its mechanism of action, Trx expression in rat heart was suppressed by direct injection of small hairpin RNA against Trx-1 (shRNA-Trx-1). Forty-eight hours after treatment, hearts were excised for isolated working-heart preparation. A group of hearts was preconditioned (PC) by subjecting them to four cyclic episodes of 5-min ischemia, each followed by 10 min of reperfusion. All the hearts, PC or non-PC, were subjected to 30-min ischemia followed by 2 h of reperfusion. As expected, the PC hearts exhibited improved ventricular function, reduced infarct size, and cardiomyocyte apoptosis. Also in PC hearts, an increase was noted in Trx-1 and other cardioprotective and redox-regulated proteins like Ref-1, phospho-Akt, and NF-kappaB DNA-binding activity. PC also caused nuclear translocation of Trx-1 and Ref-1 followed by their association. However, in hearts treated with shRNA-Trx 1, the cardioprotective effects of PC were abolished along with a concomitant decrease in nuclear localized Trx-1 and Ref-1, along with a decrease in phospho-Akt and NF-kappaB. These results demonstrate that PC triggers translocation of Trx-1 into the nucleus, where it becomes associated with Ref-1 and performs redox signaling through the activation of NF-kappaB and an increase in prosurvival signal inducer phospho-Akt.     

Oxidative stress and adaptation of the infant heart to hypoxia and ischemia

The potential contribution of oxidative stress to cardioprotection in infants induced by adaptation to chronic hypoxia and by ischemic preconditioning is poorly understood. Under conditions of oxidative stress, reactive oxygen species and reactive nitrogen species may contribute to phenotypic changes in hearts adapted to chronic hypoxia and to the pathogenesis of myocardial injury during both ischemia/reperfusion and hypoxia/reoxygenation. Hearts from infant rabbits normoxic from birth can be preconditioned by brief periods of ischemia. In contrast, hearts from infant rabbits adapted to hypoxia from birth appear resistant to ischemic preconditioning. Chronically hypoxic infant rabbit hearts are already resistant to ischemia compared with age-matched normoxic controls, and thus additional cardioprotection by ischemic preconditioning may not be possible. Endothelial nitric oxide synthase (NOS3) protein and its product nitric oxide are increased, but not NOS3 message, in chronically hypoxic infant hearts to protect against ischemia. Chronic hypoxia from birth also increases cardioprotection of infant hearts by increasing association of heat shock protein 90 with NOS3. Normoxic infant hearts also generate more superoxide by an N(omega)-nitro-L-arginine methyl ester-inhibitable mechanism than chronically hypoxic hearts. Thus, NOS3 appears to be critically important in adaptation of infant hearts to chronic hypoxia and in resistance to subsequent ischemia by regulating the production of reactive oxygen and nitrogen species.     

低浓度11,12-EET预干预对大鼠心肌缺血/再灌注损伤的影响

目的:观察外源性低浓度 11,12-EET预干预对大鼠在体心肌缺血/再灌注损伤的影响。方法:雄性Wistar大鼠,开胸,结扎和松开冠状动脉左前降支,复制心肌缺血/再灌注模型;采用缺血 5min/再灌注 5min两次造成缺血预处置。实验分 3组:对照组;缺血预处置组;外源性 11,12-EET预干预组。每组再分为A、B 2小组:A组动物心肌缺血 10min/再灌注 10min,主要观察缺血/再灌注各时程之心律失常;B组动物缺血 6 0min/再灌注 30min,主要观察缺血期心律失常、心功能的变化及再灌注后心肌梗死范围。结果:缺血预处置和 11,12-EET(6 2 4× 10^-8mol/L)预干预均可减轻缺血/再灌注心律失常及心功能的变化,降低心肌梗死范围。结论:11,12-EET预干预具有类缺血预处置样的心肌保护作用.     

Acidic preconditioning protects against ischemia-induced brain injury

Ischemic preconditioning protects against cerebral ischemia. Recent investigations indicated that acidic preconditioning (APC) protects against ischemia-induced cardiomyocytes injury. However, it is not clear whether APC can protect against cerebral ischemia. To address this issue, C57BL/6 mice were exposed 3 times at 10-min intervals to a normoxic atmosphere containing 20% CO(2) for 5 min before being further subjected to bilateral common carotid artery occlusion. APC reversed the ischemia-induced brain injury as revealed by improved performance in passive avoidance experiments and decreased neuron loss in the hippocampal CA1 region. Consistently, both APC-treated brain slices and primary cultured neurons were more resistant to oxygen-glucose-deprivation (OGD)-induced injury, in a pH- and time-dependent manner, as revealed by reversed cell/tissue viability. In addition, the APC treatment prevented OGD-induced mitochondrial transmembrane potential loss and apoptosis, which was inhibited by the mitochondrial permeability transport pore opener atractyloside. Taken together, these findings indicated that APC protects against ischemia-induced neuronal injury. The beneficial effects may be attributed, at least in part, to decreased mitochondria-dependent neuronal apoptosis.     

Préconditionnement myocardique induit par les agents anesthésiques halogènes : bases fondamentales et implications cliniques

Ischemic preconditioning (PC) is a myocardial endogenous protection against ischemia. It has been described as one or several short ischemia before a sustained ischemia. This short ischemia triggers a protective signal against this longer ischemia. An ischemic organ is able to precondition a remote organ. It is possible to replace the short ischemia by a preadministration of halogenated volatile anaesthetic with the same protective effect, this is called APC. Anaesthetic PC and ischemic PC share similar underlying biochemical mechanisms including protein kinase C, tyrosine kinase activation and mitochondrial and sarcolemnal KATP channels opening. All halogenated anaesthetics can produce an anaesthetic PC effect. Myocardial protection during reperfusion, after the long ischemia, has been shown by successive short ischemia or volatile anaesthetic administration, this is called postconditioning. Ischemic PC has been described in humans in 1993. Clinical studies in human cardiac surgery have shown the possibility of anaesthetic PC with volatile anaesthetics. These studies have shown a decrease of postoperative troponin in patient receiving halogenated anaesthetics.     

Infarct size-limiting effect of calcium preconditioning in rabbit hearts

Recent studies demonstrated that brief period of Ca2+ depletion and repletion (Ca2+ preconditioning, CPC) has strong protective effects against ischemia in a rat heart. CPC and classic preconditioning (IPC) were compared in relation with infarct size and protein kinase C (PKC) isozymes. Isolated Langendorff-perfused rabbit hearts were subjected to 45-min ischemia (Isc) followed by 120-min reperfusion (R) with or without IPC, induced by 5-min Isc and 10-min R. In the CPC hearts, 5-min Ca2+ depletion and 10-min repletion (CPC) were given before 45-min Isc, with or without concurrent PKC inhibition (calphostin C, 200 nmol/L). IPC enhanced recovery of LV function, while CPC did not. Infarct size was significantly reduced by both CPC and IPC (p < 0.05 vs. ischemic control). Membrane PKC was significantly increased from 2.53 +/- 0.07 (baseline, nmol/g tissue) to 3.11+/-0.07, 3.34 +/- 0.11, 3.15 +/- 0.09, and 3.06 +/- 0.08 by IPC, IPC and 45-min Isc, CPC and 45-min Isc, respectively (p < 0.01). Immunoblots of membrane PKC were increased by IPC, IPC and 45-min Isc, and CPC. These effects were abolished by PKC inhibition. Thus, activation of PKC may have trigger role in the mechanism of cardioprotective effect by CPC.     

Remote preconditioning,perconditioning, and postconditioning: a comparative study of their cardioprotective properties in rat models

OBJECTIVE:

Ischemia reperfusion injury is partly responsible for the high mortality associated with induced myocardial injury and the reduction in the full benefit of myocardial reperfusion. Remote ischemic preconditioning, perconditioning, and postconditioning have all been shown to be cardioprotective. However, it is still unknown which one is the most beneficial. To examine this issue, we used adult male Wistar rat ischemia reperfusion models to compare the cardioprotective effect of these three approaches applied on double-sided hind limbs.

METHODS:

The rats were randomly distributed to the following five groups: sham, ischemia reperfusion, remote preconditioning, remote perconditioning, and remote post-conditioning. The ischemia/reperfusion model was established by sternotomy followed by a 30-min ligation of the left coronary artery and a subsequent 3-h reperfusion. Remote conditioning was induced with three 5-min ischemia/5-min reperfusion cycles of the double-sided hind limbs using a tourniquet.

RESULTS:

A lower early reperfusion arrhythmia score (1.50±0.97) was found in the rats treated with remote perconditioning compared to those in the ischemia reperfusion group (2.33±0.71). Meanwhile, reduced infarct size was also observed (15.27±5.19% in remote perconditioning, 14.53±3.45% in remote preconditioning, and 19.84±5.85% in remote post-conditioning vs. 34.47±7.13% in ischemia reperfusion, p<0.05), as well as higher expression levels of the apoptosis-relevant protein Bcl-2/Bax following global (ischemia/reperfusion) injury in in vivo rat heart models (1.255±0.053 in remote perconditioning, 1.463±0.290 in remote preconditioning, and 1.461±0.541 in remote post-conditioning vs. 1.003±0.159 in ischemia reperfusion, p<0.05).

CONCLUSION:

Three remote conditioning strategies implemented with episodes of double-sided hind limb ischemia/reperfusion have similar therapeutic potential for cardiac ischemia/reperfusion injury, and remote perconditioning has a greater ability to prevent reperfusion arrhythmia.     

缺血预处理在心瓣膜置换术中对心电活动及细胞缝隙连接的保护作用

目的：从心肌细胞缝隙连接结构角度探讨缺血预处理（IP）在心脏瓣膜置换术中发挥保护作用的机制。方法：连续随机观察2004年4月-2004年12月接受心脏瓣膜置换手术治疗的患者54例，随机分成两组:IP组（n＝22）,主动脉阻断前实行单次缺血2 min开放3 min的IP方案，阻断主动脉后采用冷晶体心脏停搏液心肌保护进行手术；对照组（n＝32）,无缺血预处理，余步骤同IP组。观察两组术后心律失常发生、缝隙连接蛋白（Cx43）表达（免疫组化SABC法）以及电镜下心肌细胞结构及闰盘的变化。结果：IP组有1例（4.55%）发生室性心律失常（偶发室性早博）；11例（50.00%）室上性心律失常（房颤、房扑、各种室上速、各种房室传导阻滞）；有10例（45.50%）发生心肌缺血性ST-T段改变。对照组有14例（43.75%）发生室性心律失常（各种室性早博、心动过速）；18例（56.25%）室上性心律失常；有28例（87.50%）发生心肌缺血性ST-T段改变，两组心律失常发生率有显著差异（P<0.05）。两组术前Cx43表达阳性单位无显著差异（P>0.05）。术后IP组为16.15±4.40，较术前无显著变化（P>0.05）；对照组为11.92±1.26，较术前明显下降（P<0.05）。术后两组Cx43表达有显著差异（P<0.05）。电镜下观察：对照组闰盘不连接、紊乱、部分断裂，甚至完全断裂、崩解；心肌纤维也发生了大量坏死性结构改变：肌丝纤维肿胀，排列紊乱，肌丝Z线增宽，其它各带模糊，部分肌纤维溶解。IP组心肌细胞闰盘基本正常、连续，而心肌结构也基本正常。结论：IP维持了心肌缝隙连接蛋白Cx43的表达，具有保护细胞间缝隙连接结构和心肌电活动的正常传导作用。     

Relation between ischemic preconditioning and the duration of sustained ischemia.

It has been reported that repetitive brief periods of ischemia and reperfusion (ischemic preconditioning, IP) cause a significant reduction in the extent of myocardial necrosis or in the incidence of reperfusion arrhythmias in rat heart. However, recent reports have stated that IP effect is diminished or lost in the canine or bovine heart if ischemia (mostly regional) is sustained for 40 min or longer. The main objective of this study is to assess whether IP provides myocardial protection in prolonged sustained ischemia under the condition of global ischemia in isolated rabbit heart. The hearts were subjected to 10-60 min sustained ischemia (SI) followed by 60 min reperfusion with (IP heart) or without IP (ISCH heart). IP was induced by 4 cycles of 5 min global ischemia and 5 min reperfusion. Left ventricular function (LVF), extent of infarction (EI) and ultrastructural changes were examined. As a whole, the LVF began to recover on reperfusion but there was no significant difference in the functional parameters. However, extracellular Ca2+ concentration was lower in the ISCH hearts (p < 0.05) and the EI was significantly different between the hearts which had received 60 min SI (67% in the ISCH versus 32% in the IP heart, p < 0.01). Ultrastructural changes were homogeneous in the ISCH hearts and became irreversible in accordance with increase of the duration of ischemia, while these changes were heterogeneous and restricted in the IP heart. These results suggest that IP does not attenuate the postischemic dysfunction in prolonged ischemia but it can provide an infarct size-limiting effect and delay ultrastructural changes. This cardioprotective effect may be related to calcium homeostasis.     

The gap junction uncoupler heptanol abrogates infarct size reduction with preconditioning in mouse hearts.

BACKGROUND: Emerging evidence suggests that gap junction-mediated intercellular transmission of ions, metabolites and/or second messengers may serve as important determinants of myocyte viability. Our aim was to determine, using isolated buffer-perfused mouse hearts, whether the cardioprotection achieved with ischemic preconditioning (PC) is due in part to: (i) disruption of cell-cell coupling (manifest as a loss in the primary gap junction protein, connexin 43 [Cx43]) and resultant impaired transmission of a 'death' messenger, or conversely, (ii) transfer of a humoral 'survival' factor via existing gap junctions. METHODS: To explore the first possibility, we employed immunostaining to visualize and quantify Cx43 in hearts subjected to 212 min of PC ischemia or a matched control period. To test the converse corollary, we assessed the effect of heptanol-an agent well recognized to rapidly and reversibly uncouple gap junctions--on the reduction of infarct size (delineated by tetrazolium staining) achieved with PC. RESULTS: We found no evidence of a deficit in Cx43 immunoreactive signal in response to the PC stimulus. Area of necrosis (AN) was, as expected, reduced in hearts that received PC ischemia vs. controls (31+/-3% vs. 40+/-3% of the left ventricle [LV]; P<.01). However, treatment with heptanol rendered PC ineffective in eliciting protection (AN/LV: 42+/-1%). CONCLUSIONS: Our results suggest that gap junction-mediated transfer of an as-yet unknown 'survival' factor-rather than disrupted transfer of a 'death messenger'-may play a role in the increased resistance to infarction conferred by antecedent PC ischemia in mouse heart.     

Thioredoxin regulation of ischemic preconditioning

Thioredoxins are a class of small redox-regulating proteins that appear to play a crucial role in many oxidative stress-inducible degenerative diseases. A recent study demonstrated a reduction of thioredoxin-1 (Trx1) protein in the ischemic reperfused myocardium. When the same heart was adapted to ischemic stress by preconditioning with repeated cyclic episodes of small duration of ischemia and reperfusion, there was an increased induction of Trx1 expression. Inhibition of Trx1 expression resulted in reduced postischemic ventricular recovery and increased myocardial infarct size in the preconditioned heart. Corroborating these findings, transgenic mouse hearts overexpressing Trx1 were resistant to ischemic reperfusion injury as compared with the hearts from wild-type mice. Thus, it appears that thioredoxin plays a crucial role in cardioprotection induced by preconditioning.