Thioredoxin-interacting protein and myocardial mitochondrial function in ischemia–reperfusion injury

Cellular metabolism and reactive oxygen species (ROS) formation are interrelated processes in mitochondria and are implicated in a variety of human diseases including ischemic heart disease. During ischemia, mitochondrial respiration rates fall. Though seemingly paradoxical, reduced respiration has been observed to be cardioprotective due in part to reduced generation of ROS. Enhanced myocardial glucose uptake is considered beneficial for the myocardium under stress, as glucose is the primary substrate to support anaerobic metabolism. Thus, inhibition of mitochondrial respiration and uncoupling oxidative phosphorylation can protect the myocardium from irreversible ischemic damage. Growing evidence now positions the TXNIP/thioredoxin system at a nodal point linking pathways of antioxidant defense, cell survival, and energy metabolism. This emerging picture reveals TXNIP’s function as a regulator of glucose homeostasis and may prove central to regulation of mitochondrial function during ischemia. In this review, we summarize how TXNIP and its binding partner thioredoxin act as regulators of mitochondrial metabolism. While the precise mechanism remains incompletely defined, the TXNIP–thioredoxin interaction has the potential to affect signaling that regulates mitochondrial bioenergetics and respiratory function with potential cardioprotection against ischemic injury.     

The potential effects of anti-diabetic medications on myocardial ischemia–reperfusion injury

Heart disease and stroke account for 65% of the deaths in people with diabetes mellitus (DM). DM and hyperglycemia cause systemic inflammation, endothelial dysfunction, a hypercoagulable state with impaired fibrinolysis and increased platelet degranulation, and reduced coronary collateral blood flow. DM also interferes with myocardial protection afforded by preconditioning and postconditioning. Newer anti-diabetic agents should not only reduce serum glucose and HbA1c levels, but also improve cardiovascular outcomes. The older sulfonylurea agent, glyburide, abolishes the benefits of ischemic and pharmacologic preconditioning, but newer sulfonylurea agents, such as glimepiride, may not interfere with preconditioning. GLP-1 analogs and sitagliptin, an oral dipeptidyl peptidase IV inhibitor, limit myocardial infarct size in animal models by increasing intracellular cAMP levels and activating protein kinase A, whereas metformin protects the heart by activating AMP-activated protein kinase. Both thiazolidinediones (rosiglitazone and pioglitazone) limit infarct size in animal models. The protective effect of pioglitazone is dependent on downstream activation of cytosolic phospholipase A₂ and cyclooxygenase-2 with subsequent increased production of 15-epi-lipoxin A₄, prostacyclin and 15-d-PGJ₂. We conclude that agents used to treat DM have additional actions that have been shown to affect the ability of the heart to protect itself against ischemia–reperfusion injury in preclinical models. However, the effects of these agents in doses used in the clinical setting to minimize ischemia–reperfusion injury and to affect clinical outcomes in patients with DM have yet to be shown. The clinical implications as well as the mechanisms of protection should be further studied.     

The acute cardioprotective effect of glucocorticoid in myocardial ischemia–reperfusion injury occurring during cardiopulmonary bypass

The purpose of this study was to evaluate the acute cardioprotective effect of high-dose methylprednisolone (25 mg/kg) in the controlled in vivo model of myocardial ischemia–reperfusion injury occurring during cardiopulmonary bypass. Forty nondiabetic male patients with three-vessel disease undergoing first-time bypass surgery were enrolled for this double-blind prospective study. Patients were randomized to be given 25 mg/kg methylprednisolone (Group I) and saline (Group II) 1 h before cardiopulmonary bypass. The levels of cardiac troponin-I (cTnI) were used as a marker of myocardial tissue damage in myocardial ischemia–reperfusion injury. The cTnI levels were measured before surgery, at the second hour after cardiopulmonary bypass, at the 6th and 24th hours, and 5th day postoperatively. There was no significant difference between the two groups in respect to the duration of ischemia and reperfusion. The preoperative cTnI levels were 0.22 ± 0.29 ng/ml in Group I and 0.23 ± 0.28 ng/ml in Group II. cTnI levels increased to 2.40 ± 1.0 ng/ml in Group I and 3.19 ± 0.88 ng/ml in Group II at the 2nd hour after cardiopulmonary bypass. When the differences between T1 and T0 level that showed the amount of troponin release occurring due to ischemia–repefusion injury was calculated and then compared, there was a significant difference between Groups I and II (P = 0.024). The cTnI levels measured at 6 h after CPB were 1.98 ± 0.63 ng/ml in Group I and 2.75 ± 1.15 ng/ml in Group II (P = 0.049). cTnI levels decreased to 0.22 ± 0.10 ng/ml in Group I and 0.49 ± 0.25 ng/ml in Group II on the postoperative day 5 (P = 0.0001). Univalent regression analysis showed that preoperative high-dose corticosteroid usage decreased the troponin release in about 12% and this effect was statistically significant (R² = 0.12, P < 0.05). A single dose of intravenous methylpredisolone (25 mg/kg) given 1 h before ischemia reduced myocardial ischemia–reperfusion injury. These results demonstrated that the acute cardioprotective effect of corticosteroids has much potential in the future for reducing ischemia–reperfusion injury occurring during cardiopulmonary bypass when it is inevitable.     

Effects of N-acetylcysteine on myocardial ischemia–reperfusion injury in bypass surgery

Myocardial ischemia–reperfusion injury may complicate coronary artery bypass grafting (CABG) operations. N-Acertylcysteine (NAC) had antioxidant and microcirculatory effects, and inhibits neutrophil aggregation. The aim of this study was to determine the effects of NAC in limiting myocardial ischemia–reperfusion injury in CABG operations. Twenty patients undergoing elective coronary bypass operation with cardiopulmonary bypass were enrolled and randomly assigned to two groups: a control group operated with a routine CABG protocol, and one where NAC was administered intravenously during the operation (NAC group). Blood samples from coronary sinus for tumor necrosis factor-α assay, myocardial biopsy specimens for chemiluminescent luminol, and lucigenin measurements of reactive oxygen species were taken. The luminol (specific for ^•OH, H₂O₂, and HOCl⁻ radicals) and lucigenin (specific for O₂^•−) levels and the difference ratios after reperfusion were significantly lower in the NAC group. Tumor necrosis factor-α levels increased in the control group but, in contrast, a significant decrease was detected in the NAC group (P < 0.01). Creatine kinase-MB levels at 6 and 12 hours were singnificantly lower in the NAC group (P = 0.02). N-Acetylcysteine has potential effects to limit ischemia reperfusion injury during CABG operations. We believe that its effects on clinical outcome may be more apparent in patients prone to ischemia–reperfusion injury.     

Mitochondrial DNA damage and repair during ischemia–reperfusion injury of the heart

Ischemia–reperfusion (IR) injury of the heart generates reactive oxygen species that oxidize macromolecules including mitochondrial DNA (mtDNA). The 8-oxoguanine DNA glycosylase (OGG1) works synergistically with MutY DNA glycosylase (MYH) to maintain mtDNA integrity. Our objective was to study the functional outcome of lacking the repair enzymes OGG1 and MYH after myocardial IR and we hypothesized that OGG1 and MYH are important enzymes to preserve mtDNA and heart function after IR. Ex vivo global ischemia for 30 min followed by 10 min of reperfusion induced mtDNA damage that was removed within 60 min of reperfusion in wild-type mice. After 60 min of reperfusion the ogg1^−/− mice demonstrated increased mtDNA copy number and decreased mtDNA damage removal suggesting that OGG1 is responsible for removal of IR-induced mtDNA damage and copy number regulation. mtDNA damage was not detected in the ogg1^−/−/myh^−/−, inferring that adenine opposite 8-oxoguanine is an abundant mtDNA lesion upon IR. The level and integrity of mtDNA were restored in all genotypes after 35 min of regional ischemia and six week reperfusion with no change in cardiac function. No consistent upregulation of other mitochondrial base excision repair enzymes in any of our knockout models was found. Thus repair of mtDNA oxidative base lesions may not be important for maintenance of cardiac function during IR injury in vivo. This article is part of a Special Issue entitled "Mitochondria: From Basic Mitochondrial Biology to Cardiovascular Disease."     

Polymorphonuclear neutrophils in myocardial ischemia and reperfusion injury. Influence of coronary intervention?

Circulating polymorphonuclear neutrophils (PMNs) are known to contribute to the pathophysiology of myocardial ischemia and reperfusion injury. The present study was designed to examine whether the duration of ischemia in myocardial infarction, the type of coronary intervention (angioplasty vs. angioplasty plus stenting) and duration of the procedure itself modulate the inflammatory responses of PMNs. METHODS AND RESULTS: In patients with acute myocardial infarction (AMI; n = 20) neutrophil beta-2-integrin Mac-1 (CD11b/CD18) and L-selectin (CD62L) were determined at different time points before and after PTCA or PTCA plus stenting. After PTCA alone but not after PTCA plus stenting a significant rise in Mac-1 (136 +/- 43%) was demonstrated. This elevation decreased after 60 minutes if the duration of the recanalization procedure was shorter than 30 minutes but remained elevated after longer interventions. After delayed intervention a significant and more pronounced increase of Mac-1 (142 +/- 37%) was observed, while early intervention prevented this increase. After PTCA alone or delayed intervention a significant shedding of L-selectin (77 +/- 20%; 77 +/- 23%) was demonstrated. Early intervention or PTCA plus stenting caused no significant changes in L-selectin. CONCLUSIONS: It is concluded that PMN activation is attenuated by early and short intervention as well as by stenting. Induction of PMN activation might contribute to the superior outcome following stenting and early intervention compared to conventional PTCA in particular when performed delayed.     

Effects of intracoronary melatonin on ischemia–reperfusion injury in ST-elevation myocardial infarction

Acute coronary occlusion is effectively treated by primary percutaneous coronary intervention. However, myocardial ischemia–reperfusion injury is at the moment an unavoidable consequence of the procedure. Oxidative stress is central in the development of ischemia–reperfusion injury. Melatonin, an endogenous hormone, acts through antioxidant mechanisms and could potentially minimize the myocardial injury. The aim of the experimental study was to examine the cardioprotective effects of melatonin in a porcine closed-chest reperfused infarction model. A total of 20 landrace pigs were randomized to a dosage of 200 mg (0.4 mg/mL) melatonin or placebo (saline). The intervention was administered intracoronary and intravenous. Infarct size, area at risk and microvascular obstruction were determined ex vivo by cardiovascular magnetic resonance imaging. Myocardial salvage index was calculated. The plasma levels of high-sensitive troponin T were assessed repeatedly. The experimenters were blinded with regard to treatment regimen. Melatonin did not significantly increase myocardial salvage index compared with placebo [melatonin 21.8 % (16.1; 24.8) vs. placebo 20.2 % (16.9; 27.0), p = 1.00]. The extent of microvascular obstruction was similar between the groups [melatonin 3.8 % (2.7; 7.1) vs. placebo 3.7 % (1.3; 7.7), p = 0.96]. The area under the curve for high-sensitive troponin T release was insignificantly reduced by 32 % in the melatonin group [AUC melatonin 12,343.9 (6,889.2; 20,147.4) ng h/L vs. AUC placebo 18,285.3 (5,180.4; 23,716.8) ng h/L, p = 0.82]. Combined intracoronary and intravenous treatment with melatonin did not reduce myocardial reperfusion injury. The lack of a positive effect could be due to an ineffective dose of melatonin, a type II error or the timing of administration.     

CircularRNA CRIRTM alleviates myocardial ischemia?reperfusion injury by inhibiting the combination ofmicroRNA?1 and calmodulin

正onstrated that CRIRTM alleviates myocardial ischemia?reperfusion injury via suppressing miR?1 leading to en?     

Susceptibility to ischemia and reperfusion arrhythmias in myocardial hypertrophy: due to flow of injury current?

Left ventricle (LV) hypertrophy is associated with an increased risk of sudden death, which may be due in part to a greater vulnerability to severe ventricular arrhythmias. Our objectives were to determine (i) whether pressure overload-induced LV hypertrophy increases susceptibility to ischemia- and/or reperfusion-induced ventricular fibrillation (VF), and (ii) whether any increased susceptibility is mediated by changes intrinsic to the hypertrophied myocardium. LV pressure overload was induced in rats by abdominal aortic constriction (AC), while controls received sham-operations (SH). Three weeks after the operation, LV weight was 44 +/- 3% greater in AC rats than in SH rats although right ventricle (RV) weights were similar. At this time, isolated hearts (n = 12/group) were subjected to dual coronary perfusion. Alter 15 minutes of aerobic perfusion, either the left or right coronary bed (supplying predominantly LV or RV tissue, respectively) was subjected to 7 minutes of zero-flow ischemia and either 5 minutes of reperfusion (reperfusion study) or 40 minutes of sustained ischemia (ischemia study). AC rats exhibited greater susceptibility than SH rats to both ischemia- and reperfusion-induced ventricular fibrillation, but only when the hypertrophied LV was subjected to ischemia. The increased susceptibility to arrhythmias was not entirely due to a larger ischemic zone, indicating that intrinsic changes within hypertrophied myocarium played a role in arrhythmogenesis.     

Mechanism of TLR-4/NF-κB pathway in myocardial ischemia reperfusion injury of mouse

Objective: To detect the expression of Toll-like receptor 4(TLR-4) and NF-κB and to discuss the mechanism of TLR-4/NF-κB pathway in the myocardial ischemia reperfusion injury of mouse. Methods: TLR-4 mutant mice and wild homozygous mice were divided into the model group and sham group. Mice in the model group were given the ligation of left anterior descending coronary artery for the modeling, while mice in the sham group were not given the ligation after threading. The cardiac muscle tissues were collected for the morphological observation. The immuno histochemistry was employed to detect the expression of NF-κB, Western blot was used to detect the expression of TLR-4 and ELISA to detect the expression of serum inflammatory factors. Results: The expression of NF-κB in TLR-4 null mice after the myocardial ischemia reperfusion was significantly lower than that in wild homozygous mice. For the model group and sham group, the expression of TLR-4 in wild homozygous mice was all significantly higher than that in TLR-4 null mice, while the expression of TLR-4 in TLR-4 null mice in the model group was significantly higher than that in sham group, with the statistical difference(P0.05). The expression of inflammatory factors in TLR-4 null mice and wild homozygous mice in the model group was significantly higher than that in sham group. The expression of all factors in group A with TLR-4 null was significantly lower than that in group B with wild homozygous type, with the statistical difference(P0.05). Conclusions: TLR-4/NF-κB pathway is closely related to the myocardial ischemia reperfusion injury, which plays its role through the release of inflammatory cytokines.     

The effects of anisodamine and dobutamine on gur mucosal blood flow during gut ischemia／reperfusion

AIM：To detemine if anisodamine is able to augment mucsal perfusion during gut I/R ischemia-reperfusion METHODS:A jejunal sac was formend in Sperague Dawley rat.A Laser Doppler probe and a tonometer were inserted into the sac thich was filled with saline.The superior mesenteric artery was occluded(SMAO)for 60 minutes followed by 90 minutes of reperfusion.At the end of 60 minutes of SMAO.either 0.2mg/kg of anisodmine or dobutamine was injected into the jejunal sac.Lase Doppler mucosal blood flow and regional PCO2(PrCO2) measurements were made .RESULTS:Mucosal blood flow was significantly increased at 30,60 and 90 minutes of reperfusion(R30,R60,R90)when intraluminal anisodamine or dobutamine was present compared to intraluminal saline only(44&#177;3.3%or 48&#177;4.1%vs 37&#177;2.6%at R30,57&#177;5.0%,57&#177;5.0%or56&#177;4.7%vs45&#177;2.7%at R60,64&#177;3.3%or56&#177;4.2%.vs48&#177;3.4%at R90,respectively P&lt;0.05),Blood flow changes were also reflected by lowering of jejunal PrCO2 measurements after imtraluminal anisodamine or dobutamine compared with that of the saline controls(41&#177;3.1mmHg or 44&#177;3.0mmHg vs49&#177;3.7mmHg at R30,38&#177;3.7mmHg or 40&#177;2.1mmHg vs47&#177;3.8mmHg at R60,34&#177;2.1mmHg or 39&#177;3.0mmHg vs46&#177;3.4mmHg at R90,respectively,P&lt;0.05),Most interesting finding was that there were significantly higher mucosal blood flow and lower jejunal PrCO2 in anisodamine group than those in dobutamine group at 90 minutes of reperfusion(64&#177;3.3%vs56&#177;4.2%for blood flow or 34&#177;2.1mmHg vs39&#177;3.0mmHg for PrCOs,respectively,P&lt;0.05).suggesting that anisodamine had a more lasting effect on mucosal perfusion than dobutamine.CONCLUSION.Intraluminal anisodamine and dobutamine can augment mucosal blood flow during gut I/R and alleviate mucosal acidosis.The results provided benifical effects on the treatment of splanchnic hypoperfusion following traumatic or burn shock.     

The relationship between activation of TLR4 and partial hepatic ischemia/reperfusion injury in mice

BACKGROUND: Toil-like receptors (TLRs) are a group of evolutionarily conserved pattern recognition receptors involved in the activation of the immune system in response to various pathogens. In this study, we elucidated the relationship between activation of TLR4 and liver injury in partial hepatic ischemia/reperfusion (I/R) injury in mice. METHODS: BALB/c mice were used in a model of partial hepatic I/R injury, and the changes of TLR4 gene expression in ischemic liver lobes were detected with real-time polymerase chain reaction (RT-PCR). The levels of plasma ALT and endotoxin in the portal vein were measured. TLR4-deficient mice (C3H/Hej) and wild type mice (C3H/Heouj) were used in a model of I/R injury; liver function impairment and the level of serum TNF-α were observed. RESULTS: After one hour ischemia, the expression of TLR4 mRNA increased at the 1st, 3rd hour of reperfusion, indicating the value of △Ct(1st hour: 1.21±0.87vs. 5.85±1.07, t=13.72, P<0.01; 3rd hour: 0.85±0.92vs. 6.11±1.24, t=16.33, P<0.01). No endotoxemia developed in every group of mice. At the 3rd hour of reperfusion, the level of serum TNF-α was significantly higher than that of sham group (Hej: 152±43 pg/ml vs. 18±10pg/ml, t=5.26, P<0.01; Heouj: 249±52pg/ml vs. 25±13 pg/ml, t=7.24, P<0.01). At the 1st, 3rd hour reperfusion, the level of plasmid ALT in Hej mice was lower than that in Heouj mice (1st hour 662±106 U/Lvs. 1216±174 U/L, t=4.21, P<0.01; 3rd hour 1145±132U/L vs. 29584±187 U/L, t=13.72, P<0.01). The level of serum TNF-αwas lower than that in Heouj mice (1524.43 U/L vs. 2494±52 U/L, t=3.94, P<0.01) at the 3rd hour reperfusion. CONCLUSION: TLR4 activation causes partial hepatic I/R injury through release of TNF-α.     

Characterization of the cardiac succinylome and its role in ischemia–reperfusion injury

Succinylation refers to modification of lysine residues with succinyl groups donated by succinyl-CoA. Sirtuin5 (Sirt5) is a mitochondrial NAD⁺-dependent deacylase that catalyzes the removal of succinyl groups from proteins. Sirt5 and protein succinylation are conserved across species, suggesting functional importance of the modification. Sirt5 loss impacts liver metabolism but the role of succinylation in the heart has not been explored. We combined affinity enrichment with proteomics and mass spectrometry to analyze total succinylated lysine content of mitochondria isolated from WT and Sirt5^−/− mouse hearts. We identified 887 succinylated lysine residues in 184 proteins. 44 peptides (5 proteins) occurred uniquely in WT samples, 289 (46 proteins) in Sirt5^−/− samples, and 554 (133 proteins) were common to both groups. The 46 unique proteins in Sirt5^−/− heart participate in metabolic processes such as fatty acid β-oxidation (Eci2) and branched chain amino acid catabolism, and include respiratory chain proteins (Ndufa7, 12, 13, Dhsa). We performed label-free analysis of the peptides common to WT and Sirt5^−/− hearts. 16 peptides from 9 proteins were significantly increased in Sirt5^−/− by at least 30%. The adenine nucleotide transporter 1 showed the highest increase in succinylation in Sirt5^−/− (108.4 fold). The data indicate that succinylation is widespread in the heart and enriched in metabolic pathways. We examined whether the loss of Sirt5 would impact ischemia–reperfusion (I/R) injury and we found an increase in infarct size in Sirt5^−/− hearts compared to WT littermates (68.5⁺/₋ 1.1% Sirt5^−/− vs 39.6⁺/⁻ 6.8% WT) following 20 min of ischemia and 90-min reperfusion. We further demonstrate that I/R injury in Sirt5^−/− heart is restored to WT levels by pretreatment with dimethyl malonate, a competitive inhibitor of succinate dehydrogenase (SDH), implicating alteration in SDH activity as causative of the injury.     

Effect of tetramethylpyrazine on P-selectin and hepatic／rena ischemia and reperfusion injury in rats

AIM: To investigate the effect of tetramethylpyrazine on hepatic/renal ischemia and reperfusion injury in rats. METHODS: Hepatic/renal function, histopathological changes, and hepatic/renal P-selectin expression were studied with biochemical measurement and immunohistochemistry in hepatic/renal ischemia and reperfusion injury in rat models. RESULTS: Hepatic/renal insufficiency and histopathological damage were much less in the tetramethylpyrazine-treated group than those in the saline-treated groups. Hepatic/renal P-selectin expression was down regulated in the tetramethylpyrazine-treated group. CONCLUSION: P-selectin might mediate neutrophil infiltration and contribute to hepatic/renal ischemia and reperfusion injury. Tetramethylpyrazine might prevent hepatic/renal damage induced by ischemia and reperfusion injury through inhibition of P-selectin.     

CXCR6 deficiency ameliorated myocardial ischemia/reperfusion injury by inhibiting infiltration of monocytes and IFN-γ-dependent autophagy

Background

Emerging evidence shows that the chemokine CXCL16 plays an important role in the pathogenesis of myocardial remodeling and development of heart failure following ischemia/reperfusion (I/R) injury. CXCR6, the receptor for CXCL16, is also critically involved. However, the underlying mechanism remained uncertain, and the aim of this research was to investigate this mechanism in CXCR6 knockout (KO) mice.

Methods and results

CXCR6 KO mice and wild type (WT) mice had no overt phenotype at baseline in the absence of injury, but difference was shown in response to I/R induction. Compared with WT mice, CXCR6 KO mice exhibited a lower infarction size (31.86 ± 1.808% vs. 43.09 ± 1.519%), and better cardiac function (measured by LVEF, LVFS, + dp/dt, LVEDP, and LVSP) following I/R. Moreover, cardiac levels of IFN-γ and IFN-γ-dependent autophagy were found to be significantly attenuated in CXCR6 KO mice. Further data showed that cardiac-enhanced IFN-γ secretion was not induced by cardiomyocytes, but by infiltrated monocytes in the myocardium in response to I/R injury. In vivo injection of IFN-γ and in vitro co-cultured cardiomyocytes with CD11b + monocytes confirmed IFN-γ activated autophagic response, and induced cardiac dysfunction in a paracrine manner.

Conclusions

The study suggested that since disruption of the CXCL16/CXCR6 signaling cascade had a cardio-protective effect against I/R injury, the underlying mechanism might be that I/R triggered the infiltration of monocytes into the myocardium, and induced cardiac autophagy through CXCL16/CXCR6-dependent paracrine secretion of IFN-γ.     

The effect of mebudipine on cardiac function and activity of the myocardial nitric oxide system in ischaemia–reperfusion injury in rats

Objectives

Previous studies have suggested that failure of the synthesis of nitric oxide is involved in the pathophysiology of myocardial ischaemia–reperfusion injury. In this study, we investigated the effect of mebudipine, a new dihydropyridine calcium channel blocker, on cardiac function and activity of the myocardial nitric oxide system in ischaemia–reperfusion injury in isolated rat hearts.

Methods

Forty male Wistar rats (250–300 g) were divided into four groups (n = 10): sham, control, vehicle and drug groups. The animals were anesthetised with sodium pentobarbital (6 mg/kg intraperitoneal). The hearts were quickly removed, mounted on a Longendorff apparatus and perfused with Krebs-Henseleit solution under constant pressure at 37°C. After 20 min stabilisation period, the ischaemic groups received 30 min global ischaemia and 120 min reperfusion. For the drug and vehicle groups, before ischaemia the hearts were perfused with mebudipine (10^-3 µM) or ethanol-enriched solution (0.01%) for 25 min, respectively. Myocardial function, and creatine kinase, lactate dehydogenase and total nitric oxide metabolite (nitrite and nitrate) levels were analysed.

Results

Cardiac functions had recovered significantly in the mebudipine group (p < 0.01). Furthermore, mebudipine remarkably reduced the levels of lactate dehydogenase and creatine kinase in the coronary effluent and increased myocardial nitric oxide metabolite levels compared with the control group.

Conclusion

Our results indicate that mebudipine reduced the intensity of myocardial ischaemia–reperfusion injury, and that activation of the myocardial nitric oxide system played an important role in this regard.     

Renal ischemia/reperfusion remotely improves myocardial energy metabolism during myocardial ischemia via adenosine receptors in rabbits: effects of “remote preconditioning”

ObjectivesThis study examined the changes in myocardial energy metabolism during myocardial ischemia after “remote preconditioning” and investigated the involvement of adenosine receptors in the mechanisms of this effect.BackgroundRecent studies have indicated that a brief period of ischemia and reperfusion (ischemic preconditioning, PC) in a remote organ reduces myocardial infarct size (IS) protecting against subsequent sustained myocardial ischemia. However, the mechanisms of “remote PC” remain unclear. We assessed myocardial energy metabolism during sustained myocardial ischemia and reperfusion after renal PC (RPC), in comparison with that after myocardial PC (MPC) in open-chest rabbits. It has been established that adenosine receptors are involved in the mechanisms of MPC.MethodsRabbits that had been anesthetized with halothane were divided into six groups. The control (CNT) group underwent 40-min coronary occlusion followed by 120 min reperfusion. Before the procedure, the MPC group underwent an additional protocol of 5 min coronary artery occlusion and 20 min reperfusion, and the RPC group received a 10 min episode of renal artery occlusion and 20 min reperfusion. In additional experimental groups, 8 sulfophenyltheophylline (SPT, 10 mg/kg), an adenosine receptor inhibitor, was intravenously injected before the 40 min myocardial ischemia (SPT, MPC + SPT and RPC + SPT groups, respectively). Myocardial levels of phosphocreatine (PCr), ATP and intracellular pH (pHi) were measured by ³¹P-NMR spectroscopy.ResultsRPC and MPC delayed the decreases in ATP levels, preserved pHi during 40-min myocardial ischemia and resulted in better recovery of ATP and PCr during 120 min reperfusion compared with the controls. SPT abolished the improvement in myocardial energy metabolism and the reduction in myocardial IS caused by MPC or RPC. Myocardial IS in the CNT (n = 8), MPC (n = 9), RPC (n = 9), SPT (n = 6), MPC + SPT (n = 8) and RPC + SPT (n = 8) groups averaged 42.8 ± 3.5%, 18.2 ± 1.8%1, 19.6 ± 1.3%1, 44.9 ± 5.0%, 35.6 ± 2.7% and 34.8 ± 3.6% of the area at risk (1p < 0.05 vs. CNT), respectively.ConclusionsPC in a remote organ, similar to MPC, improved myocardial energy metabolism during ischemia and reperfusion and reduced IS in vivo by an adenosine-dependent mechanism in rabbits.