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1.
Resveratrol, a natural antioxidant and polyphenol found in grapes and wine, has been found to pharmacologically precondition the heart through the upregulation of nitric oxide (NO). To gain further insight of the role of NO in resveratrol preconditioning, mouse hearts devoid of any copies of inhibitory NO synthase (iNOS) (iNOS knockout) and corresponding wild-type hearts were perfused with 10 microM resveratrol for 15 min followed by 25 min of ischemia and 2 h of reperfusion. Control experiments were performed with wild-type and iNOS knockout hearts that were not treated with resveratrol. Resveratrol-treated wild-type mouse hearts displayed significant improvement in postischemic ventricular functional recovery compared with those of nontreated hearts. Both resveratrol-treated and nontreated iNOS knockout mouse hearts resulted in relatively poor recovery in ventricular function compared with wild-type resveratrol-treated hearts. Myocardial infarct size was lower in the resveratrol-treated wild-type mouse hearts compared with other group of hearts. In concert, a number of apoptotic cardiomyocytes was lower in the wild-type mouse hearts treated with resveratrol. Cardioprotective effects of resveratrol was abolished when the wild-type mouse hearts were simultaneously perfused with aminoguanidine, an iNOS inhibitor. Resveratrol induced the expression of iNOS in the wild-type mouse hearts, but not in the iNOS knockout hearts, after only 30 min of reperfusion. Expression of iNOS remained high even after 2 h of reperfusion. Resveratrol-treated wild-type mouse hearts were subjected to a lower amount of oxidative stress as evidenced by reduced amount of malonaldehyde content in these hearts compared with iNOS knockout and untreated hearts. The results of this study demonstrated that resveratrol was unable to precondition iNOS knockout mouse hearts, whereas it could successfully precondition the wild-type mouse hearts, indicating an essential role of iNOS in resveratrol preconditioning of the heart.  相似文献   

2.
Das S  Fraga CG  Das DK 《Free radical research》2006,40(10):1066-1075
Recent studies have demonstrated that resveratrol (trans-3,4',5-trihydroxy stilbene), a phytoalexin found in the skin and seeds of grapes, can pharmacologically precondition (PC) the heart through a nitric oxide (NO)-dependent and adenosine receptors-mediated mechanism. Since NO can induce the expression of heme oxygenase-1 (HO-1), we examined if HO-1 induction has a direct role in resveratrol-preconditioning of the heart. Eight groups of rats were studied during 7 days: (i) control rats; (ii) rats receiving resveratrol (gavage, 2.5 mg/kg); (iii) rats injected tin protoporphyrin (SnPP), a HO-1 inhibitor, i.p. on days 1, 3 and 6; (iv) rats injected 202190 (SB), a p38MAPK inhibitor, i.p. for 7 days; (v) rats injected 294002 (LY), a Akt inhibitor, i.p. for 7days; (vi) rats receiving resveratrol and SnPP; (vii) rats receiving resveratrol and SB; and (viii) rats receiving resveratrol and LY. After the treatments, the rats were sacrificed, and the hearts isolated and subjected to 30 min global ischemia followed by 2 h of reperfusion. The results shown a significant cardioprotection with resveratrol as evidenced by superior post-ischemic ventricular recovery, reduced myocardial infarct size, and decreased number of apoptotic cardiomyocytes. SnPP treatment abolished the cardioprotective effect of resveratrol. Resveratrol induced the activation of nuclear factor kappa-beta(NFkappaB), the phosphorylation of p38MAP kinase beta and Akt, as well as the inhibition of p38 MAP kinase alpha; all these effects but the activation of NFkappaB, were completely reversed by treatment with SnPP. These results indicate that resveratrol generates cardioprotection by preconditioning the heart by HO-1-mediated mechanisms, which are regulated by p38MAP kinase and Akt survival signaling, but non-dependent on NFkappaB activation.  相似文献   

3.
Recent studies demonstrated that resveratrol, a grape-derived polyphenolic phytoalexin, provides pharmacological preconditioning (PC) of the heart through a NO-dependent mechanism. Because adenosine receptors play a role in PC, we examined whether they play any role in resveratrol PC. Rats were randomly assigned to groups perfused for 15 min with 1) Krebs-Henseleit bicarbonate buffer (KHB) only; 2) KHB containing 10 microM resveratrol; 3) 10 microM resveratrol + 1 microM 8-cyclopentyl-1,3-dimethylxanthine (CPT; adenosine A(1) receptor blocker); 4) 10 microM resveratrol + 1 microM 8-(3-chlorostyryl)caffeine (CSC; adenosine A(2a) receptor blocker); 5) 10 microM resveratrol + 1 microM 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(+/-)-dihydropyridine-3,5-dicarboxylate (MRS-1191; adenosine A(3) receptor blocker); or 6) 10 microM resveratrol + 3 microM 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride [LY-294002, phosphatidylinositol (PI)3-kinase inhibitor], and groups perfused with adenosine receptor blockers alone. Hearts were then subjected to 30-min ischemia followed by 2-h reperfusion. The results demonstrated significant cardioprotection with resveratrol evidenced by improved ventricular recovery and reduced infarct size and cardiomyocyte apoptosis. CPT and MRS 1191, but not CSC, abrogated the cardioprotective abilities of resveratrol, suggesting a role of adenosine A(1) and A(3) receptors in resveratrol PC. Resveratrol induced expression of Bcl-2 and caused its phosphorylation along with phosphorylation of cAMP response element-binding protein (CREB), Akt, and Bad. CPT blocked phosphorylation of Akt and Bad without affecting CREB, whereas MRS 1191 blocked phosphorylation of all compounds, including CREB. LY-294002 partially blocked the cardioprotective abilities of resveratrol. The results indicate that resveratrol preconditions the heart through activation of adenosine A(1) and A(3) receptors, the former transmitting a survival signal through PI3-kinase-Akt-Bcl-2 signaling pathway and the latter protecting the heart through a CREB-dependent Bcl-2 pathway in addition to an Akt-Bcl-2 pathway.  相似文献   

4.
The second window of preconditioning (SWOP) induced by inhalation of volatile anesthetics has been documented in the rat heart and is triggered by nitric oxide synthase (NOS), but involvement of NOS in the mediator phase of isoflurane-induced SWOP has not been demonstrated. We tested the hypothesis that isoflurane-induced SWOP is mediated through upregulation of inducible NOS (iNOS). Rats inhaled 0.75 minimum alveolar concentration (MAC) isoflurane, 1.5 MAC isoflurane, or O2 for 2 h. After 24, 48, 72, and 96 h, the isolated heart was perfused with buffer and subjected to 30 min of ischemia followed by 2 h of reperfusion. Inhalation of 0.75 and 1.5 MAC isoflurane significantly limited infarct size after ischemia-reperfusion 24-72 h after isoflurane inhalation. The maximum effect was obtained 48 h after inhalation of 1.5 MAC isoflurane. Postischemic left ventricular function was improved only 48 h after inhalation of 1.5 MAC isoflurane. iNOS expression and activity in the heart were increased 24-72 h after inhalation of 1.5 MAC isoflurane; this increase was less pronounced after inhalation of 0.75 MAC isoflurane. A selective iNOS inhibitor, 1400W (10 microM), abolished iNOS activation and cardioprotection induced 48 h after inhalation of 1.5 MAC isoflurane. These results suggest that isoflurane inhalation induces SWOP after 24-72 h through overexpression and activation of iNOS in the rat heart.  相似文献   

5.
We have studied some hemodynamic parameters as heart rate (HR) developed pressure (DP) and maximal positive values of the first derivative of pressure (+dP/dt max) in isolated heart from control or resveratrol treated rats. In acute ex vivo experiments, resveratrol (1-100 microM) infusion in Langendorff perfused hearts did not affect contractile function in either normoxic conditions or after ischemia/reperfusion. However when semi-chronically administered by IP injection during 7 days, resveratrol which had no effect on pre-ischemic heart greatly improved post-ischemic indexes of myocardial function. Resveratrol effect is dose-dependent and seemed optimal at a plasma level of 18.5 microM. This concentration is very close to that previously shown to be optimal and non-toxic by others. These beneficial effects of resveratrol are only partly explained by its antioxidant properties as suggested by the lack of any dose-response effect on tissue malondialdehyde (MDA) levels. They are also clearly not mediated by nitric oxide (NO) elevation. When acutely infused resveratrol had no beneficial effect and therefore could not be proposed in acute scenarios of ischemia/reperfusion or stroke. However resveratrol appeared as an efficient and promising molecule in the prevention of heart dysfunction.  相似文献   

6.
To compare ischemia-reperfusion injury in males versus females under hypercontractile conditions, perfused hearts from 129J mice pretreated with 3 mmol/l Ca(2+) or 10(-8) mol/l isoproterenol +/- 10(-6) mol/l N(omega)-nitro-L-arginine methyl ester (L-NAME) were subjected to 20 min of ischemia and 40 min of reperfusion while (31)P NMR spectra were acquired. Basal contractility increased equivalently in female versus male hearts with isoproterenol- or Ca(2+) treatment. Injury was equivalent in untreated male versus female hearts but was greater in isoproterenol or Ca(2+)-treated male than female hearts, as indicated by lower postischemic contractile function, ATP, and PCr. Endothelial nitric oxide (NO) synthase (eNOS) expression was higher in female than male hearts, neuronal NOS (nNOS) did not differ, and inducible NOS (iNOS) was undetectable. Ischemic NO production was higher in female than male hearts, and L-NAME increased injury in female isoproterenol-treated hearts. In summary, isoproterenol or high Ca(2+) pretreatment increased ischemia-reperfusion injury in males more than females. eNOS expression and NO production were higher in female than male hearts, and L-NAME blocked female protection. Females were therefore protected from the detrimental effects of adrenergic stimulation and Ca(2+) loading via a NOS-mediated mechanism.  相似文献   

7.
Hypoxia from birth increases resistance to myocardial ischemia in infant rabbits. We hypothesized that increased cardioprotection in hearts chronically hypoxic from birth persists following development in a normoxic environment and involves increased activation of nitric oxide synthase (NOS) and ATP-dependent K (K(ATP)) channels. Resistance to myocardial ischemia was determined in rabbits raised from birth to 10 days of age in a normoxic (Fi(O(2)) = 0.21) or hypoxic (Fi(O(2)) = 0.12) environment and subsequently exposed to normoxia for up to 60 days of age. Isolated hearts (n = 8/group) were subjected to 30 min of global ischemia followed by 35 min of reperfusion. At 10 days of age, resistance to myocardial ischemia (percent recovery postischemic recovery left ventricular developed pressure) was higher in chronically hypoxic hearts (68 +/- 4%) than normoxic controls (43 +/- 4%). At 10 days of age, N(G)-nitro-L-arginine methyl ester (200 microM) and glibenclamide (3 microM) abolished the cardioprotective effects of chronic hypoxia (45 +/- 4% and 46 +/- 5%, respectively) but had no effect on normoxic hearts. At 30 days of age resistance to ischemia in normoxic hearts declined (36 +/- 5%). However, in hearts subjected to chronic hypoxia from birth to 10 days and then exposed to normoxia until 30 days of age, resistance to ischemia persisted (63 +/- 4%). L-NAME or glibenclamide abolished cardioprotection in previously hypoxic hearts (37 +/- 4% and 39 +/- 5%, respectively) but had no effect on normoxic hearts. Increased cardioprotection was lost by 60 days. We conclude that cardioprotection conferred by adaptation to hypoxia from birth persists on subsequent exposure to normoxia and is associated with enhanced NOS activity and activation of K(ATP) channels.  相似文献   

8.
9.
《Free radical research》2013,47(10):1173-1183
Abstract

Oxidative stress may cause a loss of tetrahydrobiopterin (BH4), a co-factor of nitric oxide synthase (NOS), decrease the bioavailability of NO and aggravate ischemia/reperfusion (I/R) injury in diabetic heart. We hypothesized that ascorbic acid (AA) and N-acetyl cysteine (NAC) protect the diabetic heart from I/R injury by increasing BH4/dihydrobiopterin (BH2) ratio and inhibiting uncoupling of NOS. Diabetes mellitus was induced in rats by streptozotocin treatment, and the hearts were isolated and perfused. BH4 and BH4/BH2 ratio decreased in the diabetic heart associated with increased production of superoxide and nitrotyrosine (NT). Treatment with AA or NAC significantly increased BH4/BH2 ratio in the diabetic heart associated with decreased production of superoxide and NT and increased generation of nitrate plus nitrite (NOx). Pre-treatment with AA or NAC before 30 min ischemia followed by 120 min reperfusion improved left ventricular (LV) function and reduced infarct size in the diabetic but not non-diabetic hearts. The NOS inhibitor, L-NAME, inhibited the increase in the generation of superoxide, NT and NOx, but aggravated LV function and increased infarct size in the diabetic heart. L-NAME also abrogated the increase in NOx and improvement of LV function and the infarct size-limiting effect induced by AA or NAC in the diabetic heart. These results suggest that AA and NAC increase BH4/BH2 ratio and prevent NOS uncoupling in the diabetic heart. Resultant increase in the bioavailability of NO renders the diabetic heart toleratant to I/R injury.  相似文献   

10.
Oxidative stress may cause a loss of tetrahydrobiopterin (BH4), a co-factor of nitric oxide synthase (NOS), decrease the bioavailability of NO and aggravate ischemia/reperfusion (I/R) injury in diabetic heart. We hypothesized that ascorbic acid (AA) and N-acetyl cysteine (NAC) protect the diabetic heart from I/R injury by increasing BH4/dihydrobiopterin (BH2) ratio and inhibiting uncoupling of NOS. Diabetes mellitus was induced in rats by streptozotocin treatment, and the hearts were isolated and perfused. BH4 and BH4/BH2 ratio decreased in the diabetic heart associated with increased production of superoxide and nitrotyrosine (NT). Treatment with AA or NAC significantly increased BH4/BH2 ratio in the diabetic heart associated with decreased production of superoxide and NT and increased generation of nitrate plus nitrite (NOx). Pre-treatment with AA or NAC before 30 min ischemia followed by 120 min reperfusion improved left ventricular (LV) function and reduced infarct size in the diabetic but not non-diabetic hearts. The NOS inhibitor, L-NAME, inhibited the increase in the generation of superoxide, NT and NOx, but aggravated LV function and increased infarct size in the diabetic heart. L-NAME also abrogated the increase in NOx and improvement of LV function and the infarct size-limiting effect induced by AA or NAC in the diabetic heart. These results suggest that AA and NAC increase BH4/BH2 ratio and prevent NOS uncoupling in the diabetic heart. Resultant increase in the bioavailability of NO renders the diabetic heart toleratant to I/R injury.  相似文献   

11.
The effect of nitric oxide (NO) synthase inhibition on apoptosis of cardiomyocytes during ischemia/reperfusion was investigated. Isolated perfused guinea-pig hearts were subjected to 35 min ischemia (I) followed by 30 min reperfusion (IR) in the presence or absence of NO synthase inhibitors, L-NAME or L-NMMA or a superoxide scavenger, SOD. Apoptosis was assessed by immunohistochemistry (TUNEL assay, Bax protein staining), by spectrophotometric measurement of cytochrome oxidase activity (COX), and by ultrastructural analysis. Inhibition of NOS significantly increased apoptosis with activation of Bax protein and decrease of COX. SOD infusion had a protective effect on these apoptotic markers. The results suggest that endogenous NO synthesis during I/R protects the heart against apoptotic cell death.  相似文献   

12.
OBJECTIVE: Previous investigations have consistently shown that the piperazine derivative trimetazidine (TMZ, 1-[2,3,4-trimethoxybenzil] piperazine, dihydrocloride) has cardioprotective effects in the experimental ischemia-reperfusion model. We tested the hypothesis that cardioprotective effect of TMZ is partly mediated by preservation of the endothelial barrier of the coronary microcirculation. METHODS: Isolated Wistar rat (250-300 g) hearts were subjected to a 15 min period of global ischemia and 180 min reperfusion in the presence or absence of 1 microM TMZ. Hemodynamic parameters, heart weight, creatinekinase (CK) release and microvascular permeability (FITC-albumin extravasation) were evaluated. In addition, eNOS gene expression was estimated by rt-PCR, and eNOS protein levels were assessed by Western analysis. In order to confirm the involvement of NO in mediating the cardioprotective effects of TMZ, 30 microM N(omega)-nitro-l-arginine methylester (L-NAME), a specific inhibitor of nitric oxide synthase, was used. RESULTS: After ischemia and reperfusion, TMZ produced a significant improvement of mechanical function associated with a reduction of CK release and FITC-albumin diffusion (P<0.001); the agent also resulted in improvement in coronary flow (at 45 min+27% vs control). The eNOS mRNA and protein levels were significantly higher in TMZ-treated hearts compared to controls. The addition of L-NAME significantly reduced the beneficial effects of TMZ on contractile function, CK release and FITC-albumin diffusion. CONCLUSIONS: in the isolated rat heart, TMZ exerts a relevant, NO-dependent, cardioprotection against ischemia-reperfusion injury and preserves the endothelial barrier of the coronary circulation. This could contribute to explain the cardioprotective action of TMZ following ischemia and reperfusion.  相似文献   

13.
Zhang H  Zhang B  Tang BY  Chen YY  Zhu L  Shen YL 《生理学报》2005,57(4):453-460
实验采用离体大鼠心脏Langendorff灌流模型,观察含巯基(卡托普利)和不含巯基(培哚普利拉)的两种血管紧张素转换酶抑制剂(angiotensin-converting enzyme inhibitors,ACEI)对抗心肌缺血的作用,并探讨一氧化氮(nitric oxide,NO)和线粒体ATP敏感性钾通道(mimchondrial ATP-sensitive potassium channel,mitoKATP channel)是否参与ACEI的心肌保护作用。结果表明:(1)给予大鼠心脏2min全心停灌和10min复灌作为闽下缺血预处理(subthreshold preconditioning,sPC)、卡托普利或培哚普利拉单独使用,均不能改善长时间缺血复灌(缺血30min+复灌120min)引起的心肌损伤。(2)当两种ACEI分别和sPC联合使用时,与sPC组相比,缺血心脏在长时间缺血后的复灌期问左室舒张末压(left ventricular end-diastolic pressure,LVEDP)明显降低,左宦发展压(left ventricular developed pressure,LVDP)和冠脉流量明显增高,乳酸脱氢酶(lactate dehydrogenase,LDH)的释放量和心肌梗死面积明显低于sPC组。(3)利用NOS抑制剂L-NAME和mitoKATP通道的抑制剂5-HD灌流10min后,可明显抑制卡托普利/培哚普利拉和sPC联合使用引起的LVEDP降低,并使LVDP和冠脉流量降低,LDH的释放量和心肌梗死面积明显增高(P〈0.05)。(4)sPC、卡托普利或培哚普利拉单独使用,心脏NO的产生增加。ACEI和sPC联合使用,与三者单独使用相比NO的浓度亦明显增高(P〈0.05)。结果提示:含与不含巯基的ACEI与闽下缺血预处理联合使用均可使大鼠心脏功能明显改善,其心肌保护作用的机制可能通过NO途径,并和mitoKATP通道的激活有关。  相似文献   

14.
15.
We have investigated the cardioprotective effects of novel tetrahydroisoquinoline nitrobenzylmercaptopurine riboside (NBMPR) analog nucleoside transport (NT) inhibitors, compounds 2 and 4, in isolated perfused rat hearts. Langendorff-perfused heart preparations were subjected to 10 min of treatment with compound 2, compound 4, or vehicle (control) followed by 30 min of global ischemia and 120 min of reperfusion. For determination of infarct size, reperfusion time was 180 min. At 1 microM, compounds 2 and 4 provided excellent cardioprotection, with left ventricular developed pressure (LVDP) recovery and end-diastolic pressure (EDP) increase of 82.9 +/- 4.0% (P<0.001) and 14.1 +/- 2.0 mmHg (P<0.03) for compound 2-treated hearts and 79.2 +/- 5.9% (P<0.002) and 7.5 +/- 2.7 mmHg (P<0.01) for compound 4-treated hearts compared with 41.6 +/- 5.2% and 42.5 +/- 6.5 mmHg for control hearts. LVDP recovery and EDP increase were 64.1 +/- 4.2% and 29.1 +/- 2.5 mmHg for hearts treated with 1 microM NBMPR. Compound 4 was the best cardioprotective agent, affording significant cardioprotection, even at 0.1 microM, with LVDP recovery and EDP increase of 76.0 +/- 4.9% (P<0.003) and 14.1 +/- 1.0 mmHg (P<0.03). At 1 microM, compound 4 and NBMPR reduced infarct size, with infarct area-to-total risk area ratios of 29.13 +/- 3.17 (P<0.001) for compound 4 and 37.5 +/- 3.42 (P<0.01) for NBMPR vs. 51.08 +/- 5.06% for control hearts. Infarct size was more effectively reduced by compound 4 than by NBMPR (P<0.02). These new tetrahydroisoquinoline NBMPR analogs are not only potent cardioprotective agents but are, also, more effective than NBMPR in this model.  相似文献   

16.
It is controversial whether nitric oxide (NO) is protective or deleterious against ischemia-reperfusion injury. We examined the effect of NO on PKC isoform translocation and protection against ischemia-reperfusion injury in perfused heart. An NO synthase inhibitor L-NAME (NG-nitro-L-arginine methyl ester, 3.0 microM), administered only during reperfusion but not during ischemia, inhibited the translocation of PKC-alpha, -delta and -epsilon isoforms to the nucleus-myofibril fraction and the translocation of PKC-alpha to the membrane fraction after ischemia (20 min) and reperfusion (10 min) in the perfused rat heart. NO donors, 3-morpholinosydnonimine (SIN-1) or S-nitroso-N-acetylpenicillamine (SNAP) activated purified PKC in vitro. SIN-1 also induced PKC isoform translocation in perfused heart. On the other hand, PKC selective inhibitor, calphostin C (0.2 microM) or chelerythrine (1.0 microM), aggravated the contractile dysfunction of ischemic heart during reperfusion, when they were perfused during reperfusion. These data suggest that NO generated during reperfusion following ischemia activates PKC isoforms and may protect the heart against contractile dysfunction in the perfused rat heart.  相似文献   

17.
Ischemic preconditioning (IPC) protects the heart against subsequent sustained ischemia reperfusion (RP). Despite many triggers and signaling pathways, which seem to be involved in IPC, the IPC-mechanisms remain a controversial issue. One of them is endogenous production of nitric oxide (NO). To assess the role of NO in IPC and its relation with glycogen and glycolysis, the effects of inhibiting NO synthase with L-NAME (50 microM) were examined in IPC rat hearts perfused with medium containing 10 mM glucose. Left ventricular developed pressure-rate product (RPP) and end diastolic pressure (EDP), lactate and glycogen contents, and cell viability were measured. Global ischemia (25 min) was followed by 30 min RP. IPC consisted in one cycle of 3 min ischemia-5 min RP. IPC reduced EDP and improved RP recovery of RPP. L-NAME had no effects on the non-IPC group but abolished these effects of IPC. IPC reduced ischemic decrease of glycogen and the acceleration of glycolysis, and improved cell viability. L-NAME did not affect these effects of IPC. The results suggest that NO is ineffective on the noxious effects of ischemia-RP in non-IPC hearts and on the effects of IPC on cell viability, glycogenolysis and glycolysis whereas it is only involved in functional protection.  相似文献   

18.
19.
Methylprednisolone (MP), a synthetic glucocorticoid, is widely used clinically and experimentally as acute antiinflammatory treatment. The molecular actions of MP indicate that pretreatment with this drug may be cardioprotective. We investigated if giving rats MP prior to excising their hearts for Langendorff-perfusion protected cardiac function against oxidative stress, and if this was mediated by increasing antioxidant defence or influencing myocardial nitric oxide synthase (NOS). Rats (n=6-11 in each group) were injected with MP (40 mg/kg i.m.) or vehicle 24 and 12 h before Langendorff-perfusion with 30 min global ischaemia and 60 min reperfusion, or 10 min perfusion with 180 μmol/L hydrogen peroxide. Other hearts were exposed to 30 min global ischaemia 5 days after MP-injection. Additional hearts were sampled before, during, and after ischaemia for analyzing tissue activity of antioxidant enzymes. Tissue endothelial and inducible NOS (eNOS and iNOS) were investigated by immunoblotting and semiquantitative RT-PCR in a time-course after MP injection. Pretreatment with MP improved left ventricular function and increased coronary flow during postischaemic reperfusion, and this effect was sustained 5 days afterwards. When exposing hearts to hydrogen peroxide, MP improved coronary flow. Catalase, glutathione peroxidase, and oxidized glutathione were increased during reperfusion of MP-treated hearts compared to vehicle only. MP did not influence eNOS at protein or mRNA level. iNOS could not be detected by immunoblotting, indicating low cardiac enzyme content. Its mRNA initially increased the first hour after injection, thereafter decreased. In conclusions, pretreating rats with MP protects the heart against ischaemia-reperfusion dysfunction. This effect could be due to increase of tissue antioxidant activity during reperfusion. MP did not influence cardiac eNOS. mRNA for iNOS was influenced by MP, but the corresponding protein could not be detected.  相似文献   

20.
The role of NO in ischemia/reperfusion injury in isolated rat heart   总被引:5,自引:0,他引:5  
Nitric oxide (NO) is an important regulator of myocardial function and vascular tone under physiological conditions. However, its role in the pathological situations, such as myocardial ischemia is not unequivocal, and both positive and negative effects have been demonstrated in different experimental settings including human pathology. The aim of the study was to investigate the role of NO in the rat hearts adapted and non-adapted to ischemia. Isolated Langendorff-perfused hearts were subjected to test ischemic (TI) challenge induced by 25 min global ischemia followed by 35 min reperfusion. Short-term adaptation to ischemia (ischemic preconditioning, IP) was evoked by 2 cycles of 5 min ischemia and 5 min reperfusion, before TI. Recovery of function at the end of reperfusion and reperfusion-induced arrhythmias served as the end-points of injury. Coronary flow (CF), left ventricular developed pressure (LVDP), and dP/dt(max) (index of contraction) were measured at the end of stabilization and throughout the remainder of the protocol until the end of reperfusion. The role of NO was investigated by subjecting the hearts to 15 min perfusion with NO synthase (NOS) inhibitor L-NAME (100 mmol/l), prior to sustained ischemia. At the end of reperfusion, LVDP in the controls recovered to 29.0 +/- 3.9 % of baseline value, whereas preconditioned hearts showed a significantly increased recovery (LVDP 66.4 +/- 5.7 %, p < 0.05). Recovery of both CF and dP/dt(max) after TI was also significantly higher in the adapted hearts (101.5 +/- 5.8 % and 83.64 +/- 3.92 % ) as compared with the controls (71.9 +/- 6.3 % and 35.7 +/- 4.87 %, respectively, p < 0.05). NOS inhibition improved contractile recovery in the non-adapted group (LVDP 53.8 +/- 3.1 %; dP/dt(max) 67.5 +/- 5.92 %) and increased CF to 82.4 +/- 5.2 %. In contrast, in the adapted group, it abolished the protective effect of IP (LVDP 31.8 +/- 3.1 %; CF 70.3 +/- 3.4 % and dP/dt(max) 43.25 +/- 2.19 %). Control group exhibited 100 % occurrence of ventricular tachycardia (VT), 57 % incidence of ventricular fibrillation (VF) - 21 % of them was sustained VF (SVF); application of L-NAME attenuated reperfusion arrhythmias (VT 70 %, VF 20 %, SVF 0 %). Adaptation by IP also reduced arrhythmias, however, L-NAME in the preconditioned hearts increased the incidence of arrhythmias (VT 100 %, VF 58 %, SVF 17 %). In conclusion: our results indicate that administration of L-NAME might be cardioprotective in the normal hearts exposed to ischemia/reperfusion (I/R) alone, suggesting that NO contributes to low ischemic tolerance in the non-adapted hearts. On the other hand, blockade of cardioprotective effect of IP by L-NAME points out to a dual role of NO in the heart: a negative role in the non-adapted myocardium subjected to I/R, and a positive one, due to its involvement in the mechanisms of protection triggered by short-term cardiac adaptation by preconditioning.  相似文献   

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