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

Hyperhomocysteinemia (HHcy) is a newly recognized risk factor for myocardial infarction, however, the effect of HHcy on endothelium-dependent flow-induced dilation of coronary arteries is not known. Thus, changes in diameter of small intramural coronary arteries (diameter, approximately 145 microm) isolated from control rats and rats with methionine diet-induced HHcy were investigated by videomicroscopy. Increases in intraluminal flow (from 0 to 40 microl/min) elicited dilations of control vessels (maximum, 25 +/- 2 microm), responses that were absent in HHcy arteries. The nitric oxide (NO) synthase inhibitor L-NAME inhibited flow-induced dilation of control coronaries, whereas it had no effect on responses of HHcy arteries. Dilations of control and HHcy arteries to the NO donor sodium nitroprusside were not different. Responses to flow in HHcy coronary arteries were unaffected by administration of L-arginine or the prostaglandin H(2)/thromboxane A(2) receptor antagonist SQ 29,548. However, in the presence of superoxide dismutase (plus catalase) or the superoxide scavenger Tiron increases in flow elicited L-NAME-sensitive dilations of HHcy coronaries (maximum, 18 +/- 5 microm). Also, superoxide dismutase significantly reduced the enhanced superoxide production of HHcy coronaries (measured by the lucigenin chemiluminescence method). Single vessel Western blotting showed an increased tyrosine nitrosation (a stable biomarker of tissue peroxynitrite formation) in HHcy coronaries. Also, extensive prevalence of 3-nitrotyrosine immunoreactivity was observed in HHcy coronaries that was confined primarily to the subendothelial layers of smooth muscle. We propose that in HHcy an increased level of superoxide scavenges NO forming peroxynitrite, which increases protein nitrosation. The reduced bioavailability of NO impairs flow-induced dilations of coronary arteries, which may contribute to the development of coronary atherosclerosis and ischemic heart disease.
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PMID:Impaired nitric oxide-mediated flow-induced coronary dilation in hyperhomocysteinemia: morphological and functional evidence for increased peroxynitrite formation. 1210 99

We studied the differences between the functional and bioenergetic effects of antioxidants (AOX) administered before or after myocardial ischemia. Sprague-Dawley rat hearts were perfused with a modified Krebs-Henseleit solution and bubbled with 95% O(2)-5% CO(2). The protocol consisted of 10 min of baseline perfusion, 20 min of global ischemia, and 30 min of reperfusion. An AOX, either 1,2-dihydroxybenzene-3,5-disulfonate (Tiron), a superoxide scavenger, or N-acetyl-L-cysteine, was infused during either baseline or reperfusion. An additional group received deferoxamine as a bolus before ischemia. Hearts were freeze-clamped at baseline, at end of ischemia, and at end of reperfusion for analysis of high-energy phosphates. All AOX, when given before ischemia, inhibited recovery of ATP compared with controls. Both Tiron and deferoxamine also inhibited recovery of phosphocreatine. AOX given before ischemia decreased the efficiency of contraction during reperfusion compared with controls. All of the changes in energetics and efficiency brought on by preischemic AOX treatment could be blocked by a preconditioning stimulus. This suggests that reactive oxygen species, which are generated during ischemia, enhance bioenergetic recovery by increasing the efficiency of contraction.
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PMID:Reactive oxygen species generated during myocardial ischemia enable energetic recovery during reperfusion. 1223 20

The link between endothelial nitric oxide synthase (eNOS) activation and vascular diameter during ischemia-reperfusion was investigated in the rat heart. After short (<30 min) and long (>45 min) time of ischemia conferred by coronary artery occlusion of the rats, reperfusion caused dilatation and constriction of arterioles, respectively. Partial oxygen pressure (pO2) measurement of the heart by the electrode confirmed the hyper-perfusion and no-reflow phenomena during reperfusion, as well as myocardial ischemia. The vascular diameter was correlated with phosphorylation of Akt and serine 1177 residue of eNOS, and formation of NO-bound guanylate cyclase (GC) by immuoflorescence study. Western blotting confirmed the phosphorylation of eNOS-Ser1177 depending on ischemia time. The constriction during reperfusion after 45 min of ischemia is supposedly caused by the inhibition of Akt-mediated eNOS-Ser1177 phosphorylation, which was suppressed by a PKC inhibitor chelerythrine, or ROS scavengers N-2-mercaptopropionyl glycine (MPG) and 4,5-Dihydroxy-1, 3-benzenedisulfonic acid disodium salt (Tiron). However, an endothelin receptor antagonist BQ123 alleviated the vasoconstriction by increasing NO availability but not eNOS-Ser1177 phosphorylation. Thus, vascular patency is correlated with eNOS-Ser1177 phosphorylation in association with ROS, and PKC during reperfusion. Endothelin inhibits vasodilatation by reducing NO availability during reperfusion.
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PMID:Endothelial NO Synthase (eNOS) phosphorylation regulates coronary diameter during ischemia-reperfusion in association with oxidative stress. 1603 23

Oxidative/nitrative stress caused by peroxynitrite, the reaction product of superoxide (O2(.-)) and nitric oxide (NO), is the primary cause of myocardial ischemia/reperfusion injury. The present study determined whether INO-4885 [5,10,15,20-tetra[N-(benzyl-4'-carboxylate)-2-pyridinium]-21H,23H-porphine iron(III) chloride], a new peroxynitrite decomposition catalyst, may provide cellular protection and protect heart from myocardial ischemia/reperfusion injury. Adult male mice were subjected to 30 min of ischemia and 3 or 24 h of reperfusion. Mice were randomized to receive vehicle, INO-4885 without catalytic moiety, or INO-4885 (3-300 microg/kg i.p.) 10 min before reperfusion. Infarct size, apoptosis, nitrotyrosine content, NO/O2(.-) production, and inducible nitric-oxide synthase (iNOS)/NADPH oxidase expression were determined. INO-4885 treatment reduced ischemia/reperfusion-induced protein nitration and caspase 3 activation in a dose-dependent fashion in the range of 3 to 100 microg/kg. However, doses exceeding 100 microg/kg produced nonspecific effects and attenuated its protective ability. At the optimal dose (30 microg/kg), INO-4885 significantly reduced infarct size (p < 0.01), decreased apoptosis (p < 0.01), and reduced tissue nitrotyrosine content (p < 0.01). As expected, INO-4885 had no effect on ischemia/reperfusion-induced iNOS expression and NO overproduction. To our surprise, this compound significantly reduced superoxide production and partially blocked NADPH oxidase overexpression in the ischemic/reperfused cardiac tissue. Additional experiments demonstrated that INO-4885 provided better cardioprotection than N-(3-(aminomethyl)benzyl)acetamidine (1400W, a selective iNOS inhibitor), apocynin (an NADPH oxidase inhibitor), or Tiron (a cell-permeable superoxide scavenger). Taken together, our data demonstrated that INO-4885 is a cardioprotective molecule that attenuates myocardial reperfusion injury by facilitating peroxynitrite decomposition and inhibiting NADPH oxidase-derived O2(.-) production.
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PMID:INO-4885 [5,10,15,20-tetra[N-(benzyl-4'-carboxylate)-2-pyridinium]-21H,23H-porphine iron(III) chloride], a peroxynitrite decomposition catalyst, protects the heart against reperfusion injury in mice. 1903 57