Effects of SEA0400, a novel inhibitor of the Na+/Ca2+ exchanger, on myocardial stunning in anesthetized dogs

Activation of the Na+/Ca2+ exchanger may contribute to Ca2+ overload during reperfusion after transient ischemia. We examined the effects of 2-[4-[(2,5-difluorophenyl) methoxy]phenoxy]-5-ethoxyaniline (SEA0400), a selective inhibitor of Na+/Ca2+ exchange, on a canine model of ischemia/reperfusion injury (myocardial stunning). Myocardial stunning was induced by a 15-min occlusion of the left anterior descending coronary artery followed by a 4-h reperfusion in anesthetized open-chest dogs. Reperfusion gradually restored myocardial percent segment shortening but remained depressed during a 4-h reperfusion period. A bolus intravenous injection of SEA0400 (0.3 or 1.0 mg/kg), given 1 min before reperfusion, improved significantly the recovery of percent segment shortening in the ischemic/reperfused myocardium. SEA0400 did not affect the hemodynamics and electrocardiogram parameters. In addition, SEA0400 did not affect reperfusion-induced change in coronary blood flow. These results suggest that the Na+/Ca2+ exchanger is involved in the stunned myocardium of dogs after reperfusion, and that SEA0400 has a protective effect against myocardial stunning in dogs.     

Brain natriuretic peptide reverses the effects of myocardial stunning in rabbit myocardium

We tested the hypothesis that brain natriuretic peptide (BNP) would decrease the effects of myocardial stunning in rabbit hearts. We also examined the mechanisms responsible for these effects. In two groups of anesthetized open-chest rabbits, myocardial stunning was produced by 2 15-min occlusions of the left anterior descending artery separated by 15 min of reperfusion. The treatment group had BNP (10(-3) mol/l) topically applied to the stunned area. Hemodynamic and functional parameters were measured. Coronary flow and O2 extraction were used to determine myocardial O2 consumption. In separate animals, we measured the function of isolated control and simulated ischemia (95% N2/5% CO2, 15 min)-reperfusion ventricular myocytes with BNP or C-type natriuretic peptide (10(-8)-10(-7) mol/l) followed by KT5823 (10(-6) mol/l, cyclic GMP protein kinase inhibitor). In the in vivo control group, baseline delay to contraction was 47+/-4 ms and after stunning it increased to 71+/-10 ms. In the treatment group, baseline delay to contraction was 40+/-7 ms, and after stunning and BNP it did not significantly increase (43+/-6 ms). Neither stunning nor BNP administration affected regional O2 consumption. In control myocytes, BNP (10(-7) mol/l) decreased the percent shortening from 6.7+/-0.4 to 4.5+/-0.2%; after KT5823 administration, the percent shortening increased to 5.4+/-0.5%. In ischemia-reperfusion myocytes, BNP (10(-7) mol/l) decreased the percent shortening less from 5.0+/-0.5 to 3.8+/-0.2%; KT5823 administration did not increase the percent shortening (3.8+/-0.2%). BNP similarly and significantly increased cyclic GMP levels in control and stunned myocytes. The data illustrated that BNP administration reversed the effects of stunning and its mechanism may be independent of the cyclic GMP protein kinase.     

Nicorandil attenuates myocardial dysfunction associated with transient ischemia by opening ATP-dependent potassium channels.

The objective of this study was to determine whether ATP-dependent potassium channel activation is involved in the mechanism by which nicorandil reduces postischemic contractile dysfunction produced by a brief period of ischemia (myocardial stunning). Barbital-anesthetized dogs were subjected to 15-min left anterior descending (LAD) coronary artery occlusion followed by 3-h reperfusion. Saline or nicorandil (100 micrograms/kg + 25 micrograms/kg/min) were infused 15 min before and throughout occlusion with or without addition of the KATP channel antagonist, glibenclamide 0.3 mg/kg as an intravenous (i.v.) bolus. Regional myocardial blood flow was measured by radioactive microspheres, and left ventricular (LV) segment function was measured by sonomicrometry. There were no significant differences between the groups in area-at-risk size or collateral blood flow. In contrast, nicorandil significantly reduced mean aortic blood pressure (BP) and the rate-pressure product (RPP) which persisted throughout the occlusion period. In addition, nicorandil markedly accelerated recovery of segment shortening in the ischemic/reperfused region as compared with control dogs. Pretreatment of dogs with glibenclamide blocked none of the hemodynamic effects of nicorandil, but it did prevent improvement in reperfusion segment function. The small dose of glibenclamide used had no effect on hemodynamics or the degree of stunning. Thus, these results suggest that nicorandil attenuates stunning in anesthetized dogs by a direct cardioprotective effect as a result of KATP channel activation in ischemic myocardium.     

Improved recovery of myocardial segment function following a short coronary occlusion in dogs by nicorandil, a potential new antianginal agent, and nifedipine

The effects of nicorandil [SG-75, 2-nicotinamidoethyl nitrate (ester)] and nifedipine on the recovery of myocardial segment shortening were compared to a vehicle-treated group following a short occlusion (15 min) of the left anterior descending coronary artery (LAD) and reperfusion (5 h). The relationship between myocardial blood flow and myocardial segment shortening was examined by means of the radioactive microsphere technique and sonomicrometry. Nicorandil (100 micrograms/kg followed by 25 micrograms/kg/min, i.v.) or nifedipine (3 micrograms/kg followed by 1 microgram/kg/min, i.v.) was administered 10 min prior to and throughout the occlusion period. Both drugs produced similar decreases in mean arterial pressure (approximately 25 mm Hg) during LAD occlusion. Similar degrees of ischemia (flow deprivation) were produced in the vehicle, nicorandil, and nifedipine groups; however, nicorandil produced a significantly greater decrease in the heart rate-left ventricular systolic pressure product during coronary occlusion. During reperfusion of the LAD there was no difference in the hemodynamics of the vehicle, nicorandil, or nifedipine groups. Neither drug altered myocardial blood flow to the ischemic region during the occlusion or reperfusion period when compared to the vehicle-treated group; however, both nicorandil and nifedipine pretreatment significantly improved recovery of percentage of segment shortening of the ischemic region. Nicorandil improved the recovery of function (percentage of segment shortening) to a greater extent than did nifedipine throughout the reperfusion period, most likely because of the greater decrease in afterload produced by nicorandil.(ABSTRACT TRUNCATED AT 250 WORDS)     

SUPEROXIDE DISMUTASE ATTENUATED POST-ISCHAEMIC CONTRACTILE DYSFUNCTION IN A MYOCARDIAL XANTHINE OXIDASE DEFICIENT SPECIES

1. We assessed the effect of polyethylene glycol conjugated superoxide dismutase (PEG-SOD) on myocardial stunning in the rabbit heart in which xanthine oxidase level is extremely low. 2. In open-chest anaesthetized rabbits, the left marginal branch of the coronary artery was occluded for 10 min and then reperfused for 30 min. A group of rabbits (PEG-SOD group) received 1000 units/kg of PED-SOD and another group (control group) was given saline 15 min before the coronary occlusion. 3. Regional systolic thickening fraction (TF) was similarly reduced to approximately -25% of baseline value during ischaemia in both groups. However recovery of TF after reperfusion was significantly better in the PEG-SOD group (n = 9) and TF at 30 min after reperfusion was 70.1 +/- 3.9% of baseline value compared with 44.9 +/- 3.4% in the control group (n = 9; P less than 0.05). Rate-pressure products, left ventricular pressure, and LV dP/dt max were not significantly different between the PEG-SOD treated and untreated control rabbits at any time during the experiment. PEG-SOD did not modify the regional myocardial blood flow (coloured microsphere method) during ischaemia/reperfusion, which was assessed by using separate groups of rabbits. 4. These findings indicate that oxygen free radicals are important in the pathogenesis of myocardial stunning in xanthine oxidase deficient hearts.     

羟基积雪草苷对兔心肌缺血再灌注损伤的保护作用

研究羟基积雪草苷(madecassoside，MC)对在体兔缺血再灌注损伤的预防保护作用，并初步探讨MC的作用机制。制备兔心肌缺血再灌注损伤(MIRI)模型；缺血前静脉滴注MC，多时间点检测心电图、血流动力学等指标；用定量组织化学染色方法计算心肌梗死面积；检测血清中酶活性及MDA含量；ELISA法测定血清中C反应蛋白(CRP)含量；TUNEL法检测心肌细胞凋亡；SP法检测细胞凋亡相关蛋白Bcl-2。预先给予MC可明显减小左心及全心心肌梗死面积；对心电图有一定的改善作用；并能明显改善心功能，降低LDH及CK的升高程度。并且，MC可明显降低CRP升高程度；升高SOD酶活性，减少MDA含量；可明显抑制MIRI引起的心肌细胞凋亡，使Bcl-2表达上调。MC对心肌缺血再灌注损伤具有明显的预防和保护作用，作用机制可能与抗脂质过氧化物产生、提高SOD活力、抗炎以及抗心肌细胞凋亡有关。     

The effects of probucol on the progression of atherosclerosis in mature Watanabe heritable hyperlipidaemic rabbits.

1. Probucol was administered to mature Watanabe heritable hyperlipidaemic (WHHL) rabbits (approximately 9 months old). Groups of WHHL rabbits were randomly selected and treated as follows: Group 1 killed at 9 months (n = 9); Group II placed on sham-treated diet at 9 months and followed for 6 months (n = 8); Group III placed on probucol at 9 months and followed for 6 months (n = 8). Probucol was administered by mixing 1% wt/wt drug with standard laboratory diet. 2. Plasma concentrations of probucol increased to 93 +/- 11 micrograms ml-1 in Group III during the initial 2 weeks and increased further to 149 +/- 24 micrograms ml-1 at the end of the treatment period. 3. Plasma concentrations of total cholesterol, unesterified cholesterol and phospholipids were significantly reduced overall by probucol, while triglycerides were not affected. 4. No statistically significant differences were observed in the presence of oxidized products in low density lipoproteins (LDL) isolated from plasma of controls compared to probucol-treated rabbits. However, LDL from probucol-treated animals was resistant to oxidation in the presence of Cu2+ (3 microM). 5. Group I had aortic atherosclerosis covering 70 +/- 5% of intimal area of thoracic aortae, that increased to 91 +/- 3% in Group II. This was associated with cholesterol contents of aortae increasing from 1.4 +/- 0.2 microgram mg-1 in Group I to 2.7 +/- 0.3 microgram mg-1 in Group II. Probucol administration did not produce a statistically significant reduction of atherosclerotic lesion area (78 +/- 7%).(ABSTRACT TRUNCATED AT 250 WORDS)     

腺苷对兔缺血-再灌注心肌的保护作用

目的;研究腺苷对兔缺血－再灌注心肌的梗死范围和心肌收缩功能的影响。方法 采用在体兔心肌缺血再灌注模型,用RM－6280多道生理记录和分析处理系统监测心肌收缩功能指标,Evans蓝－TTC法测量心肌梗塞范围,缺血再灌注前及后即刻给腺苷两组与对照组作对比分析,结果与对照组比较,腺苷预处理心肌梗死范围明显减少（P＜0．01）,左室内压峰值（LVSP）恢复率和＋dp/dtmax恢复率明显增高（P＜0．05）,心律失常发生率降低。而缺血／再灌注即刻给予腺苷,以上指标差异均无显著意义。结论 缺血前给予腺苷对再灌注心脏具有保护作用,可改善缺血－再灌注收缩功能。缩小心肌梗塞范围,减少再灌注心律失常发生率。     

Anti-arrhythmic peptide N-3-(4-hydroxyphenyl)propionyl Pro-Hyp-Gly-Ala-Gly-OH reduces dispersion of action potential duration during ischemia/reperfusion in rabbit hearts

During ischemia, cardiac gap junctions close and neighboring cells uncouple. This leads to slow conduction, increased dispersion of APD90 (duration from action potential beginning to 90% of repolarization), nonuniform anisotropy, and unidirectional conduction block, all of which favor the induction of reentry arrhythmias. It has been suggested that anti-arrhythmic peptides increase gap junction conductance during states of reduced coupling. The aim of this study was to test the effect of the anti-arrhythmic peptide N-3-(4-hydroxyphenyl)propionyl Pro-Hyp-Gly-Ala-Gly-OH (HP-5) (10(-10) ) on dispersion of epicardial APD90 during both normokalemic and hypokalemic ischemia/reperfusion in isolated perfused rabbit hearts. HP-5 did not affect average APD90, heart rate, left ventricular contractility (LVP dP/dtmax), or mean coronary flow. HP-5 significantly reduced the epicardial APD dispersion during hypokalemic ischemia (HP-5 treated: 24.1 +/- 3.4 ms, untreated: 33.9 +/- 3.1 ms, p < 0.05 versus untreated) and during normokalemic reperfusion but not during normokalemic ischemia or control conditions. In addition, among untreated hearts subjected to hypokalemic ischemia/reperfusion, seven of 10 developed ventricular fibrillation, whereas only three of nine hearts perfused with HP-5 developed ventricular fibrillation. These results show that HP-5 is able to reduce APD90 dispersion during hypokalemic ischemia in rabbit hearts.     

Lipophilic HMG-CoA reductase inhibitors increase myocardial stunning in dogs

Pretreatment of dogs with simvastatin, a lipophilic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, increases myocardial contractile dysfunction during reperfusion after ischemia (stunning), with reduction of tissue adenosine triphosphate (ATP). This was thought to be a consequence of prevention of ubiquinone biosynthesis by the lipophilic inhibitor in the myocardial cell. We examined whether other lipophilic HMG-CoA reductase inhibitors also influence myocardial stunning in dogs. Vehicle, atorvastatin (2 mg/ kg/day), fluvastatin (4 mg/kg/day), or cerivastatin (40 microg/kg/ day) was orally administered for 3 weeks. Hydrophilic pravastatin (4 mg/kg/day) also was given. After 3 weeks, pentobarbital-anesthetized dogs were subjected to 15-min left anterior descending coronary artery occlusion followed by 2-h reperfusion. Myocardial segment function was determined by sonomicrometry. Tissue levels of ATP were determined in 2-h reperfused hearts. All inhibitors significantly decreased serum cholesterol level. The three lipophilic inhibitors resulted in a worsening of segment function in the reperfused myocardium, as compared with the vehicle group. The levels of ATP in the atorvastatin, fluvastatin, and cerivastatin groups were significantly lower than that in the vehicle group. These results confirm that lipophilic HMG-CoA reductase inhibitors enhance myocardial stunning in association with ATP reduction after ischemia and reperfusion.     

Amiodarone pretreatment effects on ischemic isovolumic rat hearts: a P-31 nuclear magnetic resonance study of intracellular pH and high-energy phosphates contents evolutions.

Effects of amiodarone injected intravenously (i.v.) at two doses (10 and 20 mg/kg) on perfused isovolumic rat hearts were assessed by P-31 nuclear magnetic resonance (NMR). P-31 NMR is used to measure intracellular myocardial pH, phosphocreatine (PCr), and ATP contents time evolutions. Myocardial mechanical function is estimated by heart rate (HR), left ventricular developed pressure (LVP), and coronary flow (CF). In experimental procedure A (2-h retrograde perfusion), drug injection induced a dose-dependent bradycardia (10-20%) and a slight decrease in LVP but did not affect CF, pH, PCr, or ATP contents. Experimental procedure B consisted of 30-min stabilization, 18-min ischemia, and 72-min reperfusion. During ischemia, amiodarone did not preserve ATP and PCr pools and did not alleviate acidosis. ATP decreased to 30% of its control values, whereas the PCr peak was hardly detectable after 12 min of ischemia. After 24 min of reflow, HR, PCr, and pH of treated hearts recovered. LVP recovered after 36 min, whereas for control hearts, HR, PCr, and pH recovered after 42 min and LVP did not reach its control values at the end of reperfusion time. Faster pH recovery is explained by a preservation of Na+/K+ ATPase due to the influence of amiodarone on membrane lipid dynamics.     

红景天苷对实验性心肌缺血再灌注损伤的保护作用

目的探讨红景天苷对心肌缺血再灌注损伤的影响。方法采用冠状动脉结扎法制备大鼠急性心肌缺血模型,观察红景天苷对其心电图、心肌梗死范围以及血清中酶活性的影响。结果红景天苷可以改变缺血再灌注损伤大鼠心电图S-T段的变化幅度,降低大鼠急性心肌梗死面积,抑制血清中肌酸激酶(CK)、乳酸脱氢酶(LDH)的活性,提高超氧化物歧化酶(SOD)的活力,同时降低丙二醛(MDA)的含量。结论红景天苷对心肌缺血再灌注损伤具有较好的保护作用。     

Effects of the I(K.ATP) blockers glibenclamide and HMR1883 on cardiac electrophysiology during ischemia and reperfusion

Clinical evidence indicates an antiarrhythmic effect of sulfonylureas, which might be blunted by their vascular action. We wanted to investigate the effect of glibenclamide and the new sulfonylthiourea compound 1-[[5-[2-(5-chloro-o-anisamido)ethyl]-2-methoxyphenyl]-sulfonyl]-3 -me thylthiourea (HMR1883) on cardiac electrophysiology in the course of regional ischemia and reperfusion. Isolated rabbit hearts (Langendorff-technique) were pretreated with either vehicle (n=14), 3 micromol/l glibenclamide (n=7) or 3 micromol/l HMR1883 (n=7) before regional ischemia was induced by left coronary artery branch occlusion (45 min) followed by 45 min reperfusion. Unipolar epicardial electrocardiograms were recorded from 256 epicardial AgCl electrodes. Coronary ligation resulted in a decrease in coronary flow (CF) by 35% and in left ventricular pressure (LVP) by 40% in all series. The occluded zone was 23+/-3% in all series. Ischemia led to shortening of the epicardial activation-recovery interval (ARI) in the ischemic area, which was inhibited by both drugs especially in the early phase. In the non-ischemic area, ARIs remained stable and there was no effect of the drugs. Ischemia led to an increase in the regional difference in ARI between ischemic center and border zone. This increase was significantly inhibited by both substances during late ischemia and early reperfusion (until 15 min reperfusion). In addition, the dispersion of ARIs was reduced by both drugs during late ischemia and reperfusion. Ventricular fibrillation was observed in 7/14 (control), 0/7 (glibenclamide), and 0/7 (HMR1883). All ventricular fibrillation occurred during reperfusion. In glibenclamide but not in HMR1883-treated hearts recovery of CF upon reperfusion was significantly depressed (control: 25.5+/-4; HMR1883: 23+/-2.5; glibenclamide: 16+/-1 ml/min, values at 2 min reperfusion), while the elevation of ST-segments of the electrograms in early ischemia was fully prevented by both treatments. We conclude that both glibenclamide and HMR1883 exert an antiarrhythmic effect in this model, and reduce the shortening of the ARIs in the ischemic area, thus attenuating regional differences in ARIs between ischemic and non-ischemic area. Furthermore, unlike glibenclamide HMR1883 does not interfere with postischemic hyperemia.     

Nonsteroidal antiinflammatory drugs aggravate acute myocardial ischemia in the perfused rabbit heart: a role for prostacyclin

Myocardial ischemia was induced in perfused paced isovolumic left heart preparation of the rabbit by reducing, for a period of 40 min, the flow rate from 20 ml/min to 0.2 ml/min (severe model) and to 1 ml/min (moderate model). The relationship between prostaglandin biosynthesis and cardiac ischemic damage was evaluated in the two experimental models. The results obtained indicate that the total amount of 6-keto-PGF1 alpha generated increases with the severity of the ischemia, particularly during the 20 min of reperfusion (moderate model 81.8 +/- 13.7 ng: severe model 375 +/- 102 ng). The inhibition of the prostaglandin synthesis, prostaglandin-E2, and 6-keto-prostaglandin-F1 alpha (PGE2 and 6-keto-PGF1 alpha levels below the detection limits) by Aspirin (20 micrograms/ml) and Indomethacin (1 microgram/ml) in moderate myocardial ischemia was correlated with greater increments in resting diastolic tension (nearly 100% and 40%, respectively). This phenomenon was also associated to a further decrease on cardiac contractility and increase on coronary perfusion pressure upon reperfusion. On the contrary drugs which stimulated prostaglandin generation in myocardial tissue, such as Defibrotide (400 micrograms/ml), completely protected the organ from ischemia. U-60257 (3 micrograms/ml) and FPL-55712 (2 micrograms/ml), compounds, which respectively inhibits biosynthesis and the effects of leukotrienes, displayed a beneficial activity on this moderate model of ischemia. The present data suggests that the deleterious effect of nonsteroidal antiinflammatory drugs in low flow myocardial ischemia and reperfusion damage may be associated with removal of PGI2 and PGE2 from ischemic myocardium.     

Are all HMG-CoA reductase inhibitors protective against ischemic heart disease?

Effects of pravastatin, simvastatin, atorvastatin, fluvastatin and cerivastatin on myocardial contractile dysfunction during reperfusion after brief ischemia were examined in dogs. Pretreatment of the dog with lipophilic HMG-CoA reductase inhibitors for 3 weeks, simvastatin (2 mg/kg/day), atorvastatin (2 mg/kg/day), fluvastatin (4 mg/kg/day), and cerivastatin (40 micrograms/kg/day) worsened recovery of myocardial contraction during reperfusion after brief ischemia in association with reduced myocardial ATP level. A hydrophilic HMG-CoA reductase inhibitor, pravastatin (2 and 4 mg/kg/day), did not affect the recovery of myocardial contractile function and ATP level during reperfusion following ischemia. The lipophilic inhibitors may enter the myocardial cell, inhibit ubiquinone biosynthesis, and depress ATP generation in mitochondria, leading to worsening of the myocardial stunning after reperfusion subsequent to ischemia.     

雷米普利对糖尿病大鼠心肌缺血/再灌注损伤的保护作用

目的研究雷米普利(RAM)对糖尿病大鼠心肌缺血/再灌注损伤的保护作用。方法链脲佐菌素致糖尿病大鼠被随机分为缺血/再灌注(I/R)、缺血预适应(IPC)和RAM3组。RAM组每天用RAM(1mg·kg-1)灌胃,IPC和I/R组用等体积生理盐水灌胃。4wk后各组动物均经历心肌缺血/再灌注损伤,IPC组于缺血前行心肌缺血预适应。连续监测心电图,检测心肌梗死范围、心肌细胞凋亡、凋亡蛋白Bcl-2与Bax表达,光镜下观察心肌形态学改变。结果与I/R组比较,RAM及IPC组ST-段抬高幅度降低,室早出现时间推迟,持续时间缩短,室速、室颤发生率降低,心肌梗死范围缩小,心肌细胞凋亡减轻,Bcl-2/Bax比值升高。结论连续4wk应用RAM可减轻糖尿病大鼠心肌缺血/再灌注损伤。     

Dipyridamole induced myocardial recovery after global ischemia.

1. An experimental comparative study on isolated guinea pig hearts was carried out to determine the effect of dipyridamole added to the reperfusion solution on myocardial recovery after global ischemia. 2. After 20 min of normothermic ischemia two groups of solutions: (1) Krebs solution; (2) Krebs + dipyridamole 20 micrograms/l (10 experiments in each group) were used for reperfusion. 3. Postischemic myocardial functions (heart rate, ventricular contractility, heart work) and tissue enzymes (CPK-MB, LDH) were compared with their preischemic values. 4. Addition of dipyridamole 20 micrograms/l to reperfusion solution improved postischemic myocardial functions and decreased myocardial injury.     

Diastolic Ca2+ overload caused by Na+/Ca2+ exchanger during the first minutes of reperfusion results in continued myocardial stunning

The pathogenesis of myocardial stunning caused by brief ischemia and reperfusion remains unclear. The aim of the present study was to investigate the underlying mechanism of myocardial stunning. An isolated cell model of myocardial stunning was firstly established in isolated rat ventricular myocytes exposed to 8 min of simulated ischemia and 30 min of reperfusion, the cardiomyocyte contractile function was used to evaluate myocardial stunning. A diastolic Ca(2+) overload without significant changes in systolic Ca(2+) and the amplitude of Ca(2+) transient during the first 10 min of reperfusion played an important role in the occurrence of myocardial stunning. Decreasing Ca(2+) entry into myocardial cells with low Ca(2+) reperfusion was a very efficient way to prevent myocardial stunning. Diastolic Ca(2+) overload was closely related to the reverse mode of Na(+)/Ca(2+) exchanger (NCX) rather than L-type Ca(2+) channel. The activity of the reverse mode of NCX was found significantly higher at the initial time of reperfusion, and KB-R7943, a selective inhibitor of the reverse mode of NCX, administered at first 10 min of reperfusion rather than at the time of ischemia significantly attenuated myocardial stunning. In addition, NCX inhibition also attenuated the Ca(2+) oscillation and cardiac dysfunction when field stimulus was stopped at first 10 min of reperfusion. These data suggest that one of the important mechanisms of triggering myocardial stunning is diastolic Ca(2+) overload caused by activation of the reverse mode of NCX of cardiomyocytes during the initial period of reperfusion following brief ischemia.     

San酮对大鼠缺血再灌注损伤心肌的保护作用

AIM: To investigate the protective effect of xanthones against myocardial ischemia-reperfusion injury in rats. METHODS: Ischemia-reperfusion injury was induced by 20 min of global ischemia and 40 min of reperfusion in isolated rat hearts or 60-min coronary artery occlusion and 180-min reperfusion in vivo, respectively. Heart rate, coronary flow, left ventricular pressure (LVP), and its first derivative (+/- dp/dtmax) were recorded, and the activity of creatine kinase in coronary effluent and malondialdehyde contents in myocardial tissues were measured in vitro. The activity of serum creatine kinase and myocardium infarct size were measured in vivo. RESULTS: Xanthones (90 or 300 microg/L) caused a significant improvement of cardiac function (LVP and +/- dp/dtmax) and a decrease in the release of creatine kinase in coronary effluent as well as the level of malondialdehyde in myocardial tissues. Xanthones (0.5 or 1.0 mg/kg) also markedly decreased infarct size and the release of creatine kinase in vivo. CONCLUSION: Xanthones protect the myocardium against the damages induced by ischemia-reperfusion in rats, and the effect of xanthones may be related to the inhibition of lipid peroxidation.     

硫化氢对离体大鼠心脏缺血/再灌注损伤的影响及机制初探

目的观察内源性CSE/H2S通路的改变以及给予H2S供体对缺血/再灌注心脏的影响,探讨该通路与心脏缺血/再灌注损伤的关系及作用机制。方法采用Langendorff离体灌流装置、通过停灌30min/复灌30min方式造成Wistar大鼠心肌缺血/再灌注损伤模型;采用外源性NaHS(40μmol.L-1)分别在停灌30min前(SIR)与停灌30min后处理(IRS)对缺血/再灌注心脏的影响。记录心脏收缩期左心室内压上升的最大变化速率(+dp/dtmax)、舒张期左心室内压下降的最大变化速率(-dp/dtmax)及左室内压差(LVP=左室收缩压-左室舒张压)。采用比色法检测灌流液中乳酸脱氢酶(LDH)、心肌MDA及SOD;采用比色法检测心肌胱硫醚-γ-裂解酶(CSE)活性;采用RT-PCR方法测定心肌组织CSEmRNA表达。结果与缺血/再灌注组(I/R)30min相比,SIR组及IRS组±dp/dtmax、LVP均增高,LDH降低;I/R组MDA水平高于对照组(CON)、SIR组及IRS组(P<0.05,P<0.01);IR组SOD活性低于SIR组及IRS组(P<0.05),但与CON组差别无显著性;I/R组大鼠心肌CSE活性低于CON组(P<0.05);而大鼠心肌CSEmRNA的表达与CON组差异无显著性。结论在缺血前后给予外源性NaHS均可改善因再灌注损伤引起的心肌收缩及舒张功能障碍;其作用机制可能是通过提高心肌SOD活性,增加氧自由基清除而拮抗缺血/再灌注引起的心功能及细胞膜损伤;心肌缺血/再灌注时内源性CSE活性抑制可能与心功能障碍及细胞损伤有关。