格列吡嗪对健康新西兰白兔心肌缺血预适应的影响

目的 探讨格列吡嗪对健康新西兰白兔心肌缺血预适应的影响.方法 以健康新西兰白兔为实验对象,通过开胸结扎左冠状动脉前降支的方法建立心肌缺血预适应的动物模型.将实验动物随机分对照组,预适应组,格列吡嗪组,格列吡嗪+预适应组.实验过程中记录心电图变化,实验结束后,测血肌钙蛋白,取心脏大体TTC染色,计算心肌梗死面积,以肌钙蛋白和心肌梗死面积作为终点效应指标,评价磺脲类药物格列吡嗪对心肌缺血预适应的影响.结果 预适应组与对照组相比,实验后血肌钙蛋白、心肌梗死面积较前者明显降低,单用格列吡嗪不影响实验后血肌钙蛋白、心肌梗死面积,格列吡嗪+预适应组与预适应组相比,实验后血肌钙蛋白、心肌梗死面积无明显差异.结论 格列吡嗪对健康新西兰白兔心肌缺血预适应没有影响.     

Endocannabinoids and cannabinoid receptors in ischaemia-reperfusion injury and preconditioning

Ischaemia-reperfusion (I/R) is a pivotal mechanism of organ injury during stroke, myocardial infarction, organ transplantation and vascular surgeries. Ischaemic preconditioning (IPC) is a potent endogenous form of tissue protection against I/R injury. On the one hand, endocannabinoids have been implicated in the protective effects of IPC through cannabinoid CB1/CB2 receptor-dependent and -independent mechanisms. However, there is evidence suggesting that endocannabinoids are overproduced during various forms of I/R, such as myocardial infarction or whole body I/R associated with circulatory shock, and may contribute to the cardiovascular depressive state associated with these pathologies. Previous studies using synthetic CB1 receptor agonists or knockout mice demonstrated CB1 receptor-dependent protection against cerebral I/R injury in various animal models. In contrast, several follow-up reports have shown protection afforded by CB1 receptor antagonists, but not agonists. Excitedly, emerging studies using potent CB2 receptor agonists and/or knockout mice have provided compelling evidence that CB2 receptor activation is protective against myocardial, cerebral and hepatic I/R injuries by decreasing the endothelial cell activation/inflammatory response (for example, expression of adhesion molecules, secretion of chemokines, and so on), and by attenuating the leukocyte chemotaxis, rolling, adhesion to endothelium, activation and transendothelial migration, and interrelated oxidative/nitrosative damage. This review is aimed to discuss the role of endocannabinoids and CB receptors in various forms of I/R injury (myocardial, cerebral, hepatic and circulatory shock) and preconditioning, and to delineate the evidence supporting the therapeutic utility of selective CB2 receptor agonists, which are devoid of psychoactive effects, as a promising new approach to limit I/R-induced tissue damage.     

Involvement of opioid delta (delta)- and kappa (kappa)-receptors in ischemic preconditioning in a rat model of myocardial infarction

There is controversy in the literature regarding the involvement of opioid delta (DOP, OP1)- and kappa (KOP,OP2)-receptors in ischemic preconditioning (IPC). Previous studies on this subject in our laboratories and elsewhere have been performed on either isolated heart muscles of experimental animals, or in open-heart surgery rats. To highlight this problem, we introduced an in vivo model of myocardial infarction in rats, which not only allowed electrocardiographic and enzymatic evaluation, but also morphometric assessment of myocardial infarction. In addition to these parameters, a direct receptor ligand study was undertaken, using [3H]-DPDPE, a specific opioid delta-receptor ligand. In our pharmacodynamic studies, we used the selective opioid delta-receptor agonist D-Ala2,D-Leu5 enkephalin (DADLE) and antagonist natrindole. For the evaluation of opioid kappa-receptors, the selective opioid agonist U-50488H and antagonist nor-BNI were employed. Ischemic preconditioning showed the best beneficial effect, compared with pharmacological stimulation of either opioid delta- or kappa-receptors. In normal rat myocytes, two types of opioid delta-receptors exist, namely, low-affinity and high-affinity opioid receptors. In acute myocardial infarction (30-min ischemia), the low-affinity type opioid receptors disappeared, most likely as a result of receptor downregulation due to an excessive release of enkephalins. There was no change in the density of the high-affinity opioid receptor type, but their affinity significantly increased (p < 0.05) by 58%. The radioligand receptor studies showed that opioid delta 1-receptor type was involved not only in triggering, but also in maintaining, the preconditioned state. On the basis of our pharmacodynamic studies, we suggest that both opioid delta 1- and kappa-receptors are involved in the phenomenon of IPC, but with different effects. After 30 min of left coronary artery occlusion, opioid delta-receptor agonist DADLE decreased the infarct size/area at risk from 59.80% in control, untreated, infarcted rats, to 20.40% in treated rats, without a significant effect (p > 0.05) on the occurrence of early cardiac arrhythmias. Opioid kappa-receptor agonist U-50488H produced an opposite effect on the myocardium. It decreased the infarct size/area at risk by 44%, decreased occurrence of early arrhythmias by 77% and also decreased ventricular ectopic beats by 80%. The opioid delta- and kappa-receptor agonists used in this study significantly reduced (p < 0.05) early (2 h) postinfarction mortality by 22% and 19%, respectively. Further studies are in progress to differentiate between the role of opioid kappa 1- and kappa 2-receptors and the molecular mechanisms of the effects of both opioid delta- and kappa-receptors.     

Ischemic preconditioning: triggering role of nitric oxide-derived oxidants in isolated hearts

There is evidence that oxidants generated during ischemic preconditioning (IPC) trigger or mediate cardioprotection. We examined whether a causal relationship exists between oxidant formation during ischemic preconditioning and cardioprotection. We monitored formation of dityrosine in crystalloid-perfused guinea pig isolated hearts after a preconditioning protocol and after prolonged ischemia. Superoxide dismutase, catalase, and glutathione (SCG), or the L-arginine analogue NGnitro L-arginine methyl ester (L-NAME) were given during preconditioning. Dityrosine was observed in the coronary effluent immediately after both stimuli, but not after bracketing with SCG or L-NAME. After prolonged ischemia, dityrosine was significantly lower in the IPC group than in other groups. IPC was evidenced by improved mechanical and metabolic function on reperfusion, and by reduced infarction. These effects were abrogated by either SCG or L-NAME. These data support the hypothesis that the formation of nitric oxide-derived oxidants during ischemic preconditioning is causally related to myocardial adaptation to reperfusion injury.     

缺血预适应对体外循环血流动力学影响的临床研究

目的：比较冷停搏液与缺血预适应（IPC）加冷停搏液联合应用对先天性心脏病心内直视手术后血流动力学的影响。方法：先天性心脏病病人20例,随机分为缺血预适应组（IPC,n=10)和对照组（n=10）。IPC组在阻断升主动脉前实施缺血预适应（即3分钟缺血5分钟再灌注）,阻断升主动脉,灌注（4℃）St Thomas‘停搏液,心脏完全停跳后开始心内手术;对照组则不进行缺血预适应方案。两组均于并循前、开放升主动脉心脏复跳后300min、60min时经Swan-Ganz漂浮导管测定各项备流动力学指标,并观察心肌功能恢复情况、动脉血气及电解质变化。结果：CPB后IPC组血流动力学指标恢复快（P＜0．05）,心肌收缩有力,血压维持良好,需辅用多巴胺等强心药维持血压的病例明显少于对照组（P＜0．05）;两组动脉血气无明显变化（P＜0．05）。结论：缺血预适应加冷停搏液联合应用能促进体外循环心内直视手术后血流动力的恢复。     

Delta-opioid receptor activation mimics ischemic preconditioning in the canine heart

The role of delta-opioid receptors in mediating ischemic preconditioning (IPC) in rats, rabbits, and pigs has been well-established; however, no studies have been performed in dogs. Therefore, the purpose of the present study was to determine if activation of delta-opioid receptors can mimic the cardioprotective effects of IPC in the canine heart and to determine if a nonselective opioid receptor antagonist could block IPC. All dogs were subjected to 60 minutes of left anterior descending (LAD) coronary artery occlusion and 3 hours of reperfusion. Ischemic preconditioning was produced by one 5-minute period of ischemia 10 minutes before LAD coronary artery occlusion. Infarct size (IS) expressed as a percent of the area at risk (AAR; IS/AAR) was determined by triphenyltetrazolium staining. Two selective delta-opioid receptor (DOR) agonists, TAN-67 and BW373U86, were administered by intracoronary infusion for 30 minutes before LAD occlusion and the opioid receptor antagonist naloxone was administered 30 minutes before IPC. Both TAN-67 and BW373U86 produced significant reductions in IS/AAR similar to that of IPC (control: 28+/-2.1; TAN: 12.3+/-2.2; IPC: 9.3+/-3.0: BW: 11.7+/-2.6). Naloxone attenuated the effect of IPC (control: 28+/-2.1; naloxone: 18.2+/-4.5). These results suggest that opioid receptors are important in IPC in dogs, and stimulation of delta-opioid receptors with selective agonists can mimic the cardioprotective effects of IPC and may have therapeutic potential.     

The KATP channel blocker HMR 1883 does not abolish the benefit of ischemic preconditioning on myocardial infarct mass in anesthetized rabbits

Previous experimental studies showed that the benefit of ischemic preconditioning (IPC) is abolished by K(ATP) channel blockade with glibenclamide. However, the newly discovered K(ATP) channel blocker HMR 1883 (1-[[5-[2-(5-chloro-o-anisamido)ethyl]-methoxyphenyl]sulfonyl]-3-m ethylthiourea) shows marked antifibrillatory activity in the dose range of 3 mg/kg to 10 mg/kg i.v. in various experimental models without affecting blood glucose levels. In order to investigate in a head to head comparison glibenclamide and HMR 1883 with respect to their influence on IPC, experiments were performed in rabbits with ischemia-reperfusion using myocardial infarct mass as final read out. Male New Zealand White rabbits (2.6-3.0 kg) were subjected to 30-min occlusion of a branch of the left descending coronary artery (LAD) followed by 2-h reperfusion. For IPC experiments the LAD was additionally occluded for two periods of 5 min, each followed by 10-min reperfusion, before the long-term ischemia. Infarct mass was evaluated by TTC staining and expressed as a percentage of area at risk. Rabbits (n=7/group) were randomly selected to receive (i.v.) saline vehicle 5 min prior to the 30-min occlusion period in infarct studies without IPC or to receive glibenclamide (0.3 mg/kg) or HMR 1883 (3 mg/kg) in IPC experiments, these substances being given 5 min prior to the first preconditioning or 5 min prior to the long-term ischemia of 30 min. Myocardial risk mass as a percentage of left ventricular mass did not differ between groups. The same was true for the ratio of left ventricular mass to 100 g body weight. Myocardial infarct mass as a percentage of the area at risk in the saline vehicle group without IPC was 41+/-3%. Whereas glibenclamide significantly increased infarct mass (from 41+/-3% to 55+/-4%), HMR 1883 did not affect it. IPC reduced infarct mass from 41+/-3% to 21+/-4% (P<0.05 vs. control without IPC). Glibenclamide given prior to IPC or prior to the long-term ischemia totally abolished the IPC effect (42+/-2% and 55+/-4%, respectively; P<0.05 vs. control). In contrast, HMR 1883 under the same conditions did not affect infarct size when given prior to IPC or prior to the long-term ischemia (21+/-3% and 26+/-2%, respectively). The monophasic action potential duration (MAP50) was reduced from 103+/-3 ms under normoxic conditions to 82+/-2 ms, 5 min after ischemia in the absence of drugs. This ischemia-induced shortening of the MAP was prevented by both HMR 1883 (MAP50 103+/-3 ms) and glibenclamide (MAP50 106+/-3 ms). In conclusion, although both K(ATP) channel blockers prevented ischemia-induced shortening of MAP, HMR 1883 did not abolish the beneficial effects of IPC on myocardial infarct mass in rabbits, whereas glibenclamide totally reversed this cardioprotective effect of IPC. This suggests that the sarcolemmal ATP-sensitive potassium channels are not involved in the mechanism of IPC.     

The time course of cardioprotection induced by GR79236, a selective adenosine A1-receptor agonist, in myocardial ischaemia-reperfusion injury in the pig

The cardioprotective effects of the selective adenosine A1-receptor agonist, GR79236 (N-[(1S, trans)-2-hydroxycyclopentyl]adenosine), were examined in a porcine model of myocardial ischaemia-reperfusion injury. When pigs were subjected to a 50-min coronary artery occlusion followed by 3-h reperfusion, GR79236 (10 nmol/kg, i.v.) significantly reduced infarct size whether given 10 min before the onset of ischaemia or reperfusion. This effect was independent of the bradycardia induced by GR79236, as it was also observed in animals in which heart rate was maintained by electrical pacing. However, GR79236 administered 10 min after reperfusion did not reduce infarct size. GR79236 had no effect on the incidence or outcome of ventricular dysrhythmias in this pig model of infarction. Similarly, ischaemic preconditioning (IPC, 2 x 10-min ischaemia and 10-min reperfusion) significantly reduced infarct size. The selective adenosine A1-receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 3.3 micromol/kg, i.v.), abolished the haemodynamic and cardioprotective effects of GR79236 and the cardioprotective effects of IPC in anaesthetised pigs. In conclusion, GR79236 exerted a marked cardioprotective effect in a porcine model of myocardial ischaemia-reperfusion injury, provided that it was administered before reperfusion. This suggests that GR79236 may have clinical utility in the treatment of various aspects of ischaemic heart disease.     

Mechanisms of acetylcholine- and bradykinin-induced preconditioning

Acetylcholine (ACh) and bradykinin (BK) are potent pharmacological agents which mimic ischemic preconditioning (IPC) enabling hearts to resist infarction during a subsequent period of ischemia. The cardioprotective pathways activated by BK but not ACh may also protect when activated at reperfusion. ACh and BK stimulate Gi/o-linked receptors and ultimately mediate protection by opening mitochondrial ATP-sensitive potassium channels with the generation of reactive oxygen species that act as second messengers to activate protein kinase C (PKC). There appear to be key differences, however, in the pathways prior to potassium channel opening for these two receptors. This review aims to summarize what is currently known about pharmacological preconditioning by ACh and BK with an emphasis on differences that are seen in the signal transduction cascades. Understanding the cellular basis of protection by ACh and BK is a critical step towards developing pharmacological agents that will prevent infarction during ischemia resulting from coronary occlusion or heart attack.     

3',4'-Dihydroxyflavonol reduces infarct size and injury associated with myocardial ischaemia and reperfusion in sheep

1 The antioxidant properties of flavonols in vivo and their potential benefits in myocardial ischaemia/reperfusion (I/R) injury have been little investigated. We evaluated the ability of a synthetic flavonol, 3',4'-dihydroxyflavonol (DiOHF) to scavenge superoxide in post-I/R myocardium and to prevent myocardial I/R injury. 2 Anaesthetized sheep were studied in four groups (n=5-6): control, ischaemic preconditioning (IPC), vehicle and DiOHF (before reperfusion, 5 mg kg(-1), i.v.). The left anterior descending coronary artery was occluded distal to the second diagonal branch for 1 h followed by 2 h of reperfusion. Infarct size, myocardial function, NADPH-activated superoxide generation and biochemical markers of injury were measured. 3 DiOHF (10(-8)-10(-4) m) incubated in vitro with post-I/R myocardium from the vehicle group suppressed superoxide production dose-dependently. 4 DiOHF administered in vivo also significantly reduced superoxide generation in vitro. DiOHF and IPC markedly reduced infarct size, which was 73+/-2% of the area at risk in vehicle, 50+/-4% in DiOHF, 75+/-5% in control and 44+/-4% in IPC. Post-I/R segment shortening within the ischaemic zone was greater in DiOHF (2.3+/-0.7%; P<0.01) and IPC (1.7+/-0.5%; P<0.01) than those in corresponding controls (-1.7+/-0.4; -2.1+/-0.4%). 5 DiOHF and IPC improved coronary blood flow to the ischaemic area and preserved higher levels of nitric oxide metabolites in the venous outflow from the ischaemic zone. 6 DiOHF attenuated superoxide production in post-I/R myocardium, and significantly reduced infarct size and injury following I/R in anaesthetized sheep. The extent of protection by DiOHF is comparable to that afforded by IPC. Thus, DiOHF has clinical potential for improving recovery from acute myocardial infarction and other ischaemic syndromes.     

Vitamins for the Management of Cardiovascular Disease: A Simple Solution to a Complex Problem?

Attention is focusing on the relationship between homocysteine and cardiovascular disease and the role of vitamins in the management of this prevalent ailment. Epidemiologic studies have shown that a relationship between elevated homocysteine concentrations and cardiovascular disease may exist; however, a cause-and-effect relationship has not been proven. The B vitamins are key components of homocysteine metabolism, and the trend is toward their being increasingly prescribed for cardiovascular disease. Prescribing of antioxidant vitamins, vitamin E in particular, has increased as well. Vitamin E may decrease the risk of nonfatal myocardial infarction in patients with coronary artery disease, but its benefit in preventing fatal myocardial infarction has not been shown. Vitamin supplements are not warranted in all patients with cardiovascular disease but may have a place in therapy for selected patients.     

控制指数在水稻抗褐稻虱研究中的应用

应用昆虫生命表方法及害虫种群趋势控制指数,对新惠占1号等5个水稻品种对褐稻虱的田间抗性进行了研究,并与温室苗期抗性测定结果相印证,确定新惠占1号和“7915”为抗性品种,七桂早25、玻惠占1号为中抗品种,双桂1号为感虫品种。指出害虫种群趋势控制指数是测定和评价水稻品种抗虫性的重要指标。     

In vitro properties of an in situ forming gel for the parenteral delivery of macromolecular drugs

The purpose of this research was to (i) formulate a solution of a water-insoluble interpolymeric complex (IPC) containing poly(methacrylic acid) (PMA), 15 kDa, and poly(ethylene glycol) (PEG), 20 kDa, in a biocompatible cosolvent system; (ii) demonstrate that the IPC solution can transform into a gel, in situ, at physiological pH; and (iii) determine the ability of the gel to entrap, protect, and control the release of macromolecular drugs such as proteins and oligonucleotides. Ternary phase diagrams were prepared to identify cosolvent composition containing N-methylpyrrolidone (NMP), ethanol, and water that dissolve the IPC. IPC solutions (40, 50, or 60% w/v) each containing 1 mg of either model proteins, fluorescein isothiocyanate (FITC)-insulin and FITC-albumin, or 24-mer phosphorothioate oligonucleotides, were placed in containers that were immersed in buffer, pH 7.4. Aliquots of the buffer were sampled periodically and analyzed for the macromolecular content. In addition, in vitro bioactivity of another model protein, alpha-amylase, contained in the IPC solution was also determined. The studies demonstrated that a cosolvent containing 1:1:2 ratio of NMP/ethanol/water was most suitable for dissolving the IPC. Concentrations > 30% w/v IPC were required to form the gel, however, those mixtures containing > 60% w/v IPC could not be easily injected via 18-22 gauge needle. The gel can entrap and control the release of the model macromolecules for up to 6 days, in vitro. In addition, the gel can maintain the bioactivity of the protein, alpha-amylase, for 6 days. Therefore, an IPC gel can entrap, protect, and control the release of macromolecular drugs over a period of 6 days, in vitro, and therefore can be considered for in vivo investigation.     

In Vitro Properties of an In Situ Forming Gel for the Parenteral Delivery of Macromolecular Drugs*

The purpose of this research was to (i) formulate a solution of a water-insoluble interpolymeric complex (IPC) containing poly(methacrylic acid) (PMA), 15 kDa, and poly(ethylene glycol) (PEG), 20 kDa, in a biocompatible cosolvent system; (ii) demonstrate that the IPC solution can transform into a gel, in situ, at physiological pH; and (iii) determine the ability of the gel to entrap, protect, and control the release of macromolecular drugs such as proteins and oligonucleotides. Ternary phase diagrams were prepared to identify cosolvent composition containing N-methylpyrrolidone (NMP), ethanol, and water that dissolve the IPC. IPC solutions (40, 50, or 60% w/v) each containing 1 mg of either model proteins, fluorescein isothiocyanate (FITC)–insulin and FITC–albumin, or 24-mer phosphorothioate oligonucleotides, were placed in containers that were immersed in buffer, pH 7.4. Aliquots of the buffer were sampled periodically and analyzed for the macromolecular content. In addition, in vitro bioactivity of another model protein, α-amylase, contained in the IPC solution was also determined. The studies demonstrated that a cosolvent containing 1:1:2 ratio of NMP/ethanol/water was most suitable for dissolving the IPC. Concentrations >30% w/v IPC were required to form the gel, however, those mixtures containing >60% w/v IPC could not be easily injected via 18–22 gauge needle. The gel can entrap and control the release of the model macromolecules for up to 6 days, in vitro. In addition, the gel can maintain the bioactivity of the protein, α-amylase, for 6 days. Therefore, an IPC gel can entrap, protect, and control the release of macromolecular drugs over a period of 6 days, in vitro, and therefore can be considered for in vivo investigation.     

Characterization of a critical role for CFTR chloride channels in cardioprotection against ischemia/reperfusion injury

Aim:

To further characterize the functional role of cystic fibrosis transmembrane conductance regulator (CFTR) in early and late (second window) ischemic preconditioning (IPC)- and postconditioning (POC)-mediated cardioprotection against ischemia/reperfusion (I/R) injury.

Methods:

CFTR knockout (CFTR^−/−) mice and age- and gender-matched wild-type (CFTR^+/+) and heterozygous (CFTR^+/-) mice were used. In in vivo studies, the animals were subjected to a 30-min coronary occlusion followed by a 40-min reperfusion. In ex vivo (isolate heart) studies, a 45-min global ischemia was applied. To evaluate apoptosis, the level of activated caspase 3 and TdT-mediated dUTP-X nick end labeling (TUNEL) were examined.

Results:

In the in vivo I/R models, early IPC significantly reduced the myocardial infarct size in wild-type (CFTR^+/+) (from 40.4%±5.3% to 10.4% ±2.0%, n=8, P<0.001) and heterozygous (CFTR^+/-) littermates (from 39.4%±2.4% to 15.4% ±5.1%, n=6, P<0.001) but failed to protect CFTR knockout (CFTR^−/−) mice from I/R induced myocardial infarction (46.9%±6.2% vs 55.5%±7.8%, n=6, P>0.5). Similar results were observed in the in vivo late IPC experiments. Furthermore, in both in vivo and ex vivo I/R models, POC significantly reduced myocardial infarction in wild-type mice, but not in CFTR knockout mice. In ex vivo I/R models, targeted inactivation of CFTR gene abolished the protective effects of IPC against I/R-induced apoptosis.

Conclusion:

These results provide compelling evidence for a critical role for CFTR Cl⁻ channels in IPC- and POC-mediated cardioprotection against I/R-induced myocardial injury.     

心肌梗死动物模型研究进展

心肌梗死是一种严重危害人类健康的心血管疾病。心肌梗死动物模型的开发与应用是研究心肌梗死的机制及治疗的关键。近年来,众多学者对心肌梗死模型的制作方法、检测指标等关键问题进行了深入系统的研究,使得造模成功率、动物存活率、制作速度、制作质量等都得到了很大的提高。该文就心肌梗死模型(以整体动物模型为主)的研究现状进行综述,以促进抗心肌梗死药物的研发以及临床对心肌梗死的治疗。     

Initial therapy for mild hypertension

The treatment of mild hypertension has been a subject of controversy because its benefits versus risks are not as well established as they are for moderate to severe hypertension. Results of several studies, however, now show that treatment reduces the frequency of stroke in those with milder blood pressure elevations. New guidelines published by the Joint National Committee recommend that treatment of mild hypertension begin with either a diuretic or a beta blocker. The effect on the most common complication of mild hypertension, that is, coronary heart disease (myocardial infarction and sudden cardiac death), has, however, not been encouraging in studies in which diuretics have been used as first-line treatment. Two large-scale primary preventive studies compared the efficacy of diuretics and beta blockers in reducing coronary heart disease in hypertensive patients; results were in favor of beta blocker regimens in men. So far there is some evidence, but no hard scientific proof, that certain beta blockers offer advantages over diuretics in preventing myocardial infarction and sudden cardiac death in hypertensive patients. A major concern with the use of diuretics is the risk of hypokalemia; this can be reduced when they are combined with beta blockers.     

Down regulation of cyclooxygenase-2 is involved in delayed neuroprotection by ischemic preconditioning in rats

Aim: To examine whether the prostaglandins (PGs) pathway is involved in triggering delayed neuroprotection by ischemic preconditioning (IPC) and evaluate the effects of IPC on cyclooxygenase-2 (COX-2) expression following focal cerebral ischemia and reperfusion in rats. Methods: IPC was induced by 10min of saline infusion into the left internal carotid artery with the right common carotid artery clamped at the same time. Middle cerebral artery occlusion (MCAO) and reperfusion model was prodt:ced using intraluminal filament method. Results: IPC 48h priorto MCAO significantly reduced infarct area as compared with MCAO alone. A nonselective inhibitor of COX indomethacin (3mg/kg ip) applied 1h prior to or 1h after IPC failed to affect its protective effects. IPC had no direct effect on the cortex COX-2 mRNA and protein expression 72h later, but decreased the expression of COX-2 mRNA and protein following ischemia and reperfusion insult. Conclusion: PGs pathways was not involved in triggering delayed neuroprotection by IPC, and IPC induced down-regulation of COX-2 following focal cerebral ischemia and reperfusion in rats in vivo.