Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined whether transmyocardial revascularization (TMR) relieves myocardial ischemia by increasing regional perfusion via the transmural channels in acute canine experiments. Regional blood flow during transient coronary ligation (2 min) was compared before and 30 min after TMR, and at the third transient ischemia the mid-left ventricle (LV) was cut and immediately frozen along the short axis for the analysis of NADH fluorescence in the regions around the TMR channels. In low-resolution analysis (2-4 g tissue or 2-3 cm(2) area), regional perfusion was not significantly altered after TMR, and NADH fluorescence was observed throughout the ischemic region without significant spatial variation. High-resolution analysis (2.8 mg, 1 mm x 1 mm) revealed that the flow after TMR was lower, and NADH fluorescence was higher in the regions close to the channels (1-2 mm) than in the regions 3-4 mm away from them. Creating TMR channels did not improve the regional perfusion and rather aggravated the local ischemia in the vicinity of the channels in the immediate phase.
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PMID:Transmyocardial revascularization aggravates myocardial ischemia around the channels in the immediate phase. 1099 7

Myocardial ischemia-reperfusion is associated with bursts of reactive oxygen species (ROS) such as superoxide radicals (O(2)(-).). Membrane-associated NADH oxidase (NADHox) activity is a hypothetical source of O(2)(-)., implying the NADH concentration-to-NAD(+) concentration ratio ([NADH]/[NAD(+)]) as a determinant of ROS. To test this hypothesis, cardiac NADHox and ROS formation were measured as influenced by pyruvate or L-lactate. Pre- and postischemic Langendorff guinea pig hearts were perfused at different pyruvate/L-lactate concentrations to alter cytosolic [NADH]/[NAD(+)]. NADHox and ROS were measured with the use of lucigenin chemiluminescence and electron spin resonance, respectively. In myocardial homogenates, pyruvate (0.05, 0.5 mM) and the NADHox blocker hydralazine markedly inhibited NADHox (16 +/- 2%, 58 +/- 9%). In postischemic hearts, pyruvate (0.1-5.0 mM) dose dependently inhibited ROS up to 80%. However, L-lactate (1.0-15.0 mM) stimulated both basal and postischemic ROS severalfold. Furthermore, L-lactate-induced basal ROS was dose dependently inhibited by pyruvate (0.1-5.0 mM) and not the xanthine oxidase inhibitor oxypurinol. Pyruvate did not inhibit ROS from xanthine oxidase. The data suggest a substantial influence of cytosolic NADH on cardiac O(2)(-). formation that can be inhibited by submillimolar pyruvate. Thus cytotoxicities due to cardiac ischemia-reperfusion ROS may be alleviated by redox reactants such as pyruvate.
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PMID:Antioxidant pyruvate inhibits cardiac formation of reactive oxygen species through changes in redox state. 1104 81

In the present study the effect of L-kynurenine, kynurenic acid and quinolinic acid on the heart mitochondrial function were investigated. Mitochondria were incubated with saturating concentrations of respiratory substrates glutamate/malate (5 mmol/l), succinate (10 mmol/l) or NADH (1 mmol/l), with and without kynurenines. The concentration of kynurenines varied between 1.25 micromol/l and 10 mmol/l. From all investigated kynurenines, only kynurenic acid affected dose-dependently the respiratory parameters of heart mitochondria. Respiratory control and P/O values were reduced significantly with glutamate/malate and moderately with succinate as substrates in the presence of 125 micromol/l to 10 mmol/l kynurenic acid. A known elevation of L-kynurenine in the blood of patients with ischemic heart disease or essential hypertension may suggest the involvement of L-kynurenine metabolites in the impairment of heart mitochondrial function, for example in cardiomyopathy.
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PMID:Kynurenic acid influences the respiratory parameters of rat heart mitochondria. 1117 83

Adrenochrome is an oxidative product of adrenaline and possesses cardiotoxic properties. As oxygen free radicals play a role in the cytotoxic effects of catecholamines, the role of superoxide anion radicals, as mediators of adrenochrome toxicity, was investigated using electrically-driven Langendorff rabbit hearts with depleted catecholamine stores. Repetitive regional myocardial ischemia (MI) was induced by coronary artery branch ligature, and MI was quantitated from epicardial NADH-fluorescence photography. Adrenochrome (10(-6) mol/l) was added to the perfusion solution after a reperfusion period of 20 min, 30 min before the 2nd coronary occlusion, with or without the additional application of SOD (30 U/ml). Left ventricular pressure was significantly enhanced by adrenochrome (p < 0.05), but it fell rapidly down below its initial value (p < 0.05). Coronary flow was significantly decreased by adrenochrome (p < 0.05). Whereas epicardial NADH-fluorescence was similar after repetitive coronary occlusions in untreated controls, it was significantly enhanced by adrenochrome (p < 0.05). The deleterious effects of adrenochrome on MI were not inhibited by SOD. Thus, there is no evidence for superoxide anion radicals as mediators of the deleterious effects of adrenochrome on MI in isolated rabbit hearts. The deleterious effects of adrenochrome on MI in isolated rabbit hearts might be caused by functional effects, impairing the oxygen consumption/oxygen supply balance.
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PMID:Studies on the role of superoxide anion radicals for the cardiotoxicity of adrenochrome. 1179 43

A moderate reduction in coronary blood flow results in decreased myocardial oxygen consumption, accelerated glycolysis, decreased pyruvate oxidation, and lactate accumulation. To quantitatively understand cardiac metabolism during ischemia, we have developed a mechanistic, mathematical model based on biochemical mass balances and reaction kinetics in cardiac cells. By numerical solution of model equations, computer simulations showed the dynamic responses in glucose, fatty acid, glucose-6-phosphate, glycogen, triglyceride, pyruvate, lactate, acetyl-CoA, and free-CoA as well as CO2, O2, phosphocreatine/creatine, nicotinamide adenine dinucleotide (reduced form)/nicotinamide adenine dinucleotide (oxidized form) (NADH/NAD+), and adenosine diphosphate/adenosine triphosphate (ADP/ATP). When myocardial ischemia was simulated by a 60% reduction in coronary blood flow, the model generated myocardial concentrations, uptakes, and fluxes that were consistent with experimental data from in vivo pig studies. After 60 min of ischemia the concentrations of glycogen, phosphocreatine, and ATP were decreased by 60%, 75%, and 50%, respectively. With the onset of ischemia, myocardial lactate concentration increased and the myocardium switched from net consumer to net producer of lactate. Our model predicted a rapid 13-fold increase in NADH/NAD+, but only a twofold increase in the ratio of acetyl-CoA to free-CoA. These findings are consistent with the concept that pyruvate oxidation is inhibited during ischemia partially by the rise in NADH/NAD+.
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PMID:Mechanistic model of myocardial energy metabolism under normal and ischemic conditions. 1196 72

The mitochondrial respiratory chain is a major source of reactive oxygen species (ROS) under pathological conditions including myocardial ischemia and reperfusion. Limitation of electron transport by the inhibitor rotenone immediately before ischemia decreases the production of ROS in cardiac myocytes and reduces damage to mitochondria. We asked if ROS generation by intact mitochondria during the oxidation of complex I substrates (glutamate, pyruvate/malate) occurred from complex I or III. ROS production by mitochondria of Sprague-Dawley rat hearts and corresponding submitochondrial particles was studied. ROS were measured as H2O2 using the amplex red assay. In mitochondria oxidizing complex I substrates, rotenone inhibition did not increase H2O2. Oxidation of complex I or II substrates in the presence of antimycin A markedly increased H2O2. Rotenone prevented antimycin A-induced H2O2 production in mitochondria with complex I substrates but not with complex II substrates. Catalase scavenged H2O2. In contrast to intact mitochondria, blockade of complex I with rotenone markedly increased H2O2 production from submitochondrial particles oxidizing the complex I substrate NADH. ROS are produced from complex I by the NADH dehydrogenase located in the matrix side of the inner membrane and are dissipated in mitochondria by matrix antioxidant defense. However, in submitochondrial particles devoid of antioxidant defense ROS from complex I are available for detection. In mitochondria, complex III is the principal site for ROS generation during the oxidation of complex I substrates, and rotenone protects by limiting electron flow into complex III.
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PMID:Production of reactive oxygen species by mitochondria: central role of complex III. 1284 17

Glycolysis supplements energy synthesis at high cardiac workloads, producing not only ATP but also cytosolic NADH and pyruvate for oxidative ATP synthesis. Despite adequate Po(2), speculation exists that not all cytosolic NADH is oxidized by the mitochondria, leading to lactate production. In this study, we elucidate the mechanism for limited cytosolic NADH oxidation and increased lactate production at high workload despite adequate myocardial blood flow and oxygenation. Reducing equivalents from glycolysis enter mitochondria via exchange of mitochondrial alpha-ketoglutarate (alpha-KG) for cytosolic malate. This exchange was monitored at baseline and at high workloads by comparing (13)C enrichment between the products of alpha-KG oxidation (succinate) and alpha-KG efflux from mitochondria (glutamate). Under general anesthesia, a left thoracotomy was performed on 14 dogs and [2-(13)C]acetate was infused into the left anterior descending artery for 40 min. The rate-pressure product was 9,035 +/- 1,972 and 21,659 +/- 5,266 mmHg.beats.min(-1) (n = 7) at baseline (n = 7) and with dobutamine, respectively. (13)C enrichment of succinate was 57 +/- 10% at baseline and 45 +/- 13% at elevated workload (not significant), confirming oxidation of [2-(13)C]acetate. However, cytosolic glutamate enrichment, a marker of cytosolic NADH transfer to mitochondria, was dramatically reduced at high cardiac workload (11 +/- 1%) vs. baseline (50 +/- 14%, P < 0.05). This reduced exchange of (13)C from alpha-KG to cytosolic glutamate at high work indicates reduced shuttling of cytosolic reducing equivalents into the mitochondria. Myocardial tissue lactate increased 78%, countering this reduced oxidation of cytosolic NADH. The findings elucidate a contributing mechanism to glycolysis outpacing glucose oxidation in the absence of myocardial ischemia.
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PMID:Limited transfer of cytosolic NADH into mitochondria at high cardiac workload. 1475 56

Complex I, a key component of the mitochondrial respiratory chain, exhibits diminished activity as a result of cardiac ischemia/reperfusion. Cardiac ischemia/reperfusion is associated with increases in the levels of mitochondrial Ca(2+) and pro-oxidants. In the current in vitro study, we sought evidence for a mechanistic link between Ca(2+), pro-oxidants, and inhibition of complex I utilizing mitochondria isolated from rat heart. Our results indicate that addition of Ca(2+) to solubilized mitochondria results in loss in complex I activity. Ca(2+) induced a maximum decrease in complex I activity of approximately 35% at low micromolar concentrations over a narrow physiologically relevant pH range. Loss in activity required reducing equivalents in the form of NADH and was not reversed upon addition of EGTA. The antioxidants N-acetylcysteine and superoxide dismutase, but not catalase, prevented inhibition, indicating the involvement of superoxide anion (O2(*-)) in the inactivation process. Importantly, the sulfhydryl reducing agent DTT was capable of fully restoring complex I activity implicating the formation of sulfenic acid and/or disulfide derivatives of cysteine in the inactivation process. Finally, complex I can reactivate endogenously upon Ca(2+) removal if NADH is present and the enzyme is allowed to turnover catalytically. Thus, the present study provides a mechanistic link between three alterations known to occur during cardiac ischemia/reperfusion, mitochondrial Ca(2+) accumulation, free radical production, and complex I inhibition. The reversibility of these processes suggests redox regulation of Ca(2+) handling.
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PMID:Modulation of mitochondrial complex I activity by reversible Ca2+ and NADH mediated superoxide anion dependent inhibition. 1522 60

A new multidomain mathematical model of cardiac cellular metabolism was developed to simulate metabolic responses to reduced myocardial blood flow. The model is based on mass balances and reaction kinetics that describe transport and metabolic processes of 31 key chemical species in cardiac tissue. The model has three distinct domains (blood, cytosol, and mitochondria) with interdomain transport of chemical species. In addition to distinguishing between cytosol and mitochondria, the model includes a subdomain in the cytosol to account for glycolytic metabolic channeling. Myocardial ischemia was induced by a 60% reduction in coronary blood flow, and model simulations were compared with experimental data from anesthetized pigs. Simulations with a previous model without compartmentation showed a slow activation of glycogen breakdown and delayed lactate production compared with experimental results. The addition of a subdomain for glycolysis resulted in simulations showing faster rates of glycogen breakdown and lactate production that closely matched in vivo experimental data. The dynamics of redox (NADH/NAD+) and phosphorylation (ADP/ATP) states were also simulated. These controllers are coupled to energy transfer reactions and play key regulatory roles in the cytosol and mitochondria. Simulations showed a similar dynamic response of the mitochondrial redox state and the rate of pyruvate oxidation during ischemia. In contrast, the cytosolic redox state displayed a time response similar to that of lactate production. In conclusion, this novel mechanistic model effectively predicted the rapid activation of glycogen breakdown and lactate production at the onset of ischemia and supports the concept of localization of glycolysis to a subdomain of the cytosol.
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PMID:Mechanistic model of cardiac energy metabolism predicts localization of glycolysis to cytosolic subdomain during ischemia. 1568 93

Organic nitrates have been used clinically in the treatment of ischemic heart disease for more than a century. Recently, xanthine oxidase (XO) has been reported to catalyze organic nitrate reduction under anaerobic conditions, but questions remain regarding the initial precursor of nitric oxide (NO) and the link of organic nitrate to the activation of soluble guanylyl cyclase (sGC). To characterize the mechanism of XO-mediated biotransformation of organic nitrate, studies using electron paramagnetic resonance spectroscopy, chemiluminescence NO analyzer, NO electrode, and immunoassay were performed. The XO reducing substrates xanthine, NADH, and 2,3-dihydroxybenz-aldehyde triggered the reduction of organic nitrate to nitrite anion (NO2-). Studies of the pH dependence of nitrite formation indicated that XO-mediated organic nitrate reduction occurred via an acid-catalyzed mechanism. In the absence of thiols or ascorbate, no NO generation was detected from XO-mediated organic nitrate reduction; however, addition of L-cysteine or ascorbate triggered prominent NO generation. Studies suggested that organic nitrite (R-O-NO) is produced from XO-mediated organic nitrate reduction. Further reaction of organic nitrite with thiols or ascorbate leads to the generation of NO or nitrosothiols and thus stimulates the activation of sGC. Only flavin site XO inhibitors such as diphenyleneiodonium inhibited XO-mediated organic nitrate reduction and sGC activation, indicating that organic nitrate reduction occurs at the flavin site. Thus, organic nitrite is the initial product in the process of XO-mediated organic nitrate biotransformation and is the precursor of NO and nitrosothiols, serving as the link between organic nitrate and sGC activation.
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PMID:Xanthine oxidase catalyzes anaerobic transformation of organic nitrates to nitric oxide and nitrosothiols: characterization of this mechanism and the link between organic nitrate and guanylyl cyclase activation. 1569 23


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