Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ischemia may increase glutamate release, which can lead to neuronal damage. The therapeutic value of drugs that antagonize glutamate's effects are being investigated in CNS ischemia. This study examined the efficacy of a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten- 5,10-imine hydrogen maleate], in reducing ischemic injury. We explored the limits of this therapy and different properties of MK-801 that might be involved in its neuroprotective actions. Two focal CNS ischemia models were used, a multiple cerebral embolic model (MCEM) and a rabbit spinal cord ischemia model (RSCIM). When animals were treated 5 minutes after the onset of injury, MK-801 was effective in reducing ischemic damage in both models. However, when treatment was delayed 10 minutes after the ischemic insult in the MCEM, no neuroprotection was observed even when the MK-801 dose was increased eightfold. We also did not find a beneficial effect of MK-801 pretreatment with a dose that was one tenth of the effective dose in the RSCIM. Studies using the (-) MK-801 isomer showed that MK-801 neuroprotection exhibited stereoselectivity. The contribution of anticonvulsant activity and sedation to MK-801's neuroprotective actions was examined indirectly using phenytoin and midazolam, respectively. Neither drug was effective in reducing ischemic injury in the MCEM. This suggests that MK-801's neuroprotective efficacy in ischemia is mediated through its NMDA receptor antagonist activity independent of its anticonvulsant or sedative properties. These results support the hypothesis that excessive NMDA receptor excitation may be involved in ischemic neuronal damage.
 ...
PMID:Pharmacologic studies of the neuroprotective actions of a glutamate antagonist in ischemia. 183 96

Hydroperoxide-initiated chemiluminescence was standardized as a microassay to evaluate the occurrence of oxidative stress in human biopsies. Samples of 10 to 50 mg of rat liver or heart were homogenized, diluted in reaction medium, added with tert-butyl hydroperoxide, and assayed for chemiluminescence in a liquid scintillation counter in the out-of-coincidence mode. Optimal conditions for the assay were: 0.3 to 1.2 mg/mL of homogenate protein in 120 mM KCl, 30 mM phosphate buffer (pH 7.4), and 3 mM tert-butyl hydroperoxide at 30 degrees C. In these conditions, maximal chemiluminescence values were 550 +/- 30 and 1100 +/- 40 cps/mg protein, for liver and heart homogenates, respectively. Liver and heart homogenates were subjected to in vitro oxidative stresses such as supplementation with organic hydroperoxide or with enzymatic systems generating superoxide anion or hydrogen peroxide. Chemiluminescence was higher in the poststress samples than in the control ones. The ratio: poststress chemiluminescence/control chemiluminescence (B/A) was about 1.4 or higher for both tissues. Human heart biopsies were utilized to investigate the occurrence of oxidative stress after clinical situations associated to ischemia-reperfusion. B/A ratios were 2.1 +/- 0.4, 1.4 +/- 0.1, and 2.8 +/- 0.4 for human heart, liver, and skeletal muscle, respectively.
 ...
PMID:Hydroperoxide-initiated chemiluminescence: an assay for oxidative stress in biopsies of heart, liver, and muscle. 184 67

During partial ischemia, sodium and potassium ions exchange across the blood-brain barrier, resulting in a net increase in cations and brain edema. Since this exchange is likely mediated by specific transporters such as Na,K-ATPase in the capillary endothelium and because brain capillary Na,K-ATPase activity is stimulated by increased extracellular potassium in vitro, this study was designed to determine if the rate of blood to brain sodium transport is increased in ischemic tissue having an elevated interstitial fluid potassium concentration ([K]ISF) in vivo. Sprague-Dawley rats were studied between 2-3 h after occlusion of the right middle cerebral artery. To identify where cortical tissue with an elevated [K]ISF could be sampled for transport studies, the regional pattern of cerebral blood flow and [K]ISF was obtained in a group of 17 rats using hydrogen clearance and potassium-selective microelectrode techniques. We observed severely elevated [K]ISF (greater than 10 mM) when CBF was less than 20 ml 100 g-1 min-1 and mildly elevated levels at CBF between 20-45 ml 100 g-1 min-1. In a second group of seven rats, permeability-surface area products (PS products) for 22Na and [3H]alpha-aminoisobutyric acid ([3H]AIB) were determined in ischemic cortex with elevated [K]ISF and in nonischemic cortex. The PS products for AIB were similar in both tissues (2.2 +/- 0.7 and 2.1 +/- 0.4 microliters/g/min) while the PS products for sodium was significantly increased in the ischemic tissue (1.5 +/- 0.2 and 2.4 +/- 1.1 microliters/g/min).(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Blood to brain sodium transport and interstitial fluid potassium concentration during early focal ischemia in the rat. 184 10

To study the roles of platelet-activating factor, polymorphonuclear leukocytes, and oxygen free radicals in myocardial reperfusion injury, we subjected 10 sheep to 90 minutes of mid-left anterior descending coronary artery followed by 6 hours of reperfusion. Stainings with gentian violet and tetratriphenyl ammonium chloride demonstrated 20% +/- 3% of the left ventricular mass at risk for ischemia, of which 75% +/- 10% underwent infarction. Coronary sinus blood was assayed for platelet-activating factor and neutrophil hydrogen peroxide production before and during coronary occlusion and during reperfusion. Platelet-activating factor was isolated by column chromatography and lipid extraction and quantified by radioimmunoassay. Neutrophil hydrogen peroxide production was measured by a 2',7'-dichlorofluorescein flow-cytometric assay. Platelet-activating factor was elevated to 899 +/- 210 pg/ml at 15 minutes of reperfusion, compared with the preocclusion level of 271 +/- 55 pg/ml and coronary occlusion level of 359 +/- 64 pg/ml (p less than 0.05; analysis of variance). Neutrophil hydrogen peroxide production, measured on a relative fluorescence scale, was also elevated to a level of 141 +/- 27 at 1 hour of reperfusion, compared with the preocclusion level of 103 +/- 6 and the coronary occlusion level of 114 +/- 13 (p less than 0.01; analysis of variance). Both of these parameters returned toward baselines at the end of 6 hours of reperfusion. Histologic examination revealed infiltration of polymorphonuclear leukocytes into the interstitium of the reperfused myocardium. Neutrophils isolated from unoperated and healthy sheep demonstrated a graded dose response in hydrogen peroxide production when stimulated by purified platelet-activating factor in vitro. These findings suggest that platelet-activating factor is released in the coronary circulation and is a mediator of oxygen free radical production in polymorphonuclear leukocytes during myocardial reperfusion.
 ...
PMID:Myocardial reperfusion injury. Platelet-activating factor stimulates polymorphonuclear leukocyte hydrogen peroxide production during myocardial reperfusion. 186 3

To determine the distribution and extent of myocardial edema resulting from ischemia and reperfusion, seven open-chest dogs underwent occlusion of the left circumflex coronary artery for 2 hours (group I), and 10 underwent occlusion for 2 hours and reperfusion for 2 hours (group II). Proton nuclear magnetic resonance spectroscopy (T1 and T2 relaxation times) and percent water content were determined to quantitate the amount of edema. There was a transmural increase of the T1 relaxation time of the central ischemic zone in groups I and II, although this increase was significantly greater in group II in both the subendocardium (group I = 707.8 +/- 12.5 msec, group II = 813.2 +/- 36.2 msec; p less than 0.01) and subepicardium (group I = 641.7 +/- 20.5 msec, group II = 760.5 +/- 34.7 msec; p less than 0.01). These increases were also observed in the T2 weighted relaxation time in the subendocardium (group I = 54.7 +/- 0.8 msec, group II = 78.7 +/- 6.3 msec; p less than 0.005) and subepicardium (group I = 54.0 +/- 1.4 msec, group II = 73.1 +/- 4.0 msec; p less than 0.001). Transmural differences were evident between the myocardial layers with increased T1 relaxation times (p less than 0.01) in the subendocardium in both groups. Similar increases were noted in the percent water content of the myocardium. Thus T1 and T2 relaxation times lengthened with an increase in myocardial water content following occlusion, and these relaxation times were augmented by reperfusion. We conclude that ischemia-induced edema occurs in a transmural distribution from subendocardium to subepicardium following occlusion, and this edema is further enhanced by reperfusion.
 ...
PMID:Transmural distribution of myocardial edema by NMR relaxometry following myocardial ischemia and reperfusion. 187 42

Reperfusion in the heart represents an important form of tissue injury, particularly in view of the emerging importance of reperfusion protocols aimed at salvaging the ischemic myocardium. Both the manifestations and the causes of reperfusion injury are multifold. With respect to the former, reperfusion injury can be characterized by various abnormalities including development of arrhythmias, contractile dysfunction, ultrastructural damage as well as various defects in intracellular biochemical homeostasis. The mechanisms underlying myocardial reperfusion injury are equally complex, but most likely involve numerous processes acting in concert resulting in eventual cell death. In this review, a description of various such potential mechanisms, which represent primary interests of the author, are presented. An understanding of these mechanisms has led to novel pharmacological approaches towards the protection of the reperfused myocardium. For instance, several lines of evidence implicate enhanced eicosanoid, and in particular prostaglandin, synthesis in reperfusion injury, since (1) such injury is involved with enhanced prostaglandin biosynthesis, (2) inhibition of prostaglandin synthesis with various nonsteroidal anti-inflammatory drugs attenuates injury, and (3) exogenous prostaglandins increase injury. Another intracellular process that is emerging as an important contributor to reperfusion injury in the heart is the Na+/H+ exchanger, which is most likely activated upon reperfusion. Such activation would lead to numerous intracellular disturbances including the increased synthesis of prostaglandins and elevated intracellular Ca2+ concentrations. Indeed, inhibitors of Na+/H+ exchange such as amiloride have been shown to effectively inhibit reperfusion injury. Reperfusion is also associated with depressed mitochondrial function, particularly in subsarcolemmal mitochondria which are rapidly injured as a result of both ischemic and reperfusion conditions. Preservation of mitochondrial function with dissimilar approaches such as carnitine or phosphatidylcholine administration markedly reduces reperfusion injury-. A nonpharmacological novel approach towards the protection of the reperfused myocardium represents the induction of so-called stress or heart shock proteins in the heart prior to initiation of ischemia and reperfusion. The salutary effect of the heat shock response may be dependent not on the heat shock proteins themselves, but through the concomitant elevation of tissue catalase content resulting in enhanced detoxification of intracellular hydrogen peroxide. Thus reperfusion injury represents numerous complex events such that manipulations aimed at limiting such injury can be initiated to prevent specific defects with the ultimate goal of an overall reduction in cell damage.
 ...
PMID:The 1990 Merck Frosst Award. Ischemic and reperfusion injury in the heart. Cellular mechanisms and pharmacological interventions. 191 18

It has been suggested that the sudden presence of oxygen during reperfusion after a period of ischemia may be toxic for the myocardial cell. The oxygen molecule is capable of producing reactions in the cell, forming highly reactive free radicals, and inducing lipid peroxidation of membranes, altering their integrity and increasing their fluidity and permeability. The ischemic and reperfused cardiac cell is the prime candidate for this reaction sequence and may explain the molecular mechanism underlying the pathologic events related to membrane dysfunction and calcium homeostasis. However, the myocardium has a series of defense mechanisms including the enzymes superoxide dismutase (SOD), catalase, and glutathione peroxidase plus other endogenous antioxidants such as vitamin E, ascorbic acid, and cysteine to protect the cell against the cytotoxic oxygen metabolites. The prerequisite for oxygen free radical involvement in ischemia and reperfusion damage is that ischemia alters the defense mechanisms against oxygen toxicity. It is known that ischemia may impair mitochondrial SOD and, with reperfusion, oxidative stress may occur as shown by tissue accumulation and release of oxidized glutathione. This tripeptide molecule in the cofactor of glutathione peroxidase, the enzyme that removes hydrogen and lipid peroxides. Its formation and subsequent release is a reliable index of oxidative damage. In our study, we investigated the effects of N-acetylcysteine on oxidative damage in the isolated rabbit heart. N-acetylcysteine increases, in a dose-dependent manner (from 10(-7) to 10(-5) M), the myocardial glutathione content and provides an important degree of protection against ischemia and reperfusion. Oxidative stress does not occur, mitochondrial function is maintained, enzyme release is reduced, and contractile recovery is increased. Similarly, we administered N-acetylcysteine in the pulmonary artery of coronary artery disease patients undergoing coronary bypass grafting (150 mg/kg in 1 hour followed by 150 mg/kg in 4 hours). The degree of oxidative stress on reperfusion was reduced and recovery of cardiac function improved. In this article, we review the cardioprotective role of thiol-containing agents.
 ...
PMID:Oxygen free radicals and myocardial damage: protective role of thiol-containing agents. 192 19

Gastric mucosal blood flow and its regulating factors were studied in normal and stressed rats. In addition, vascular regulating factors and the role of CoQ10 anion radical and SOD (superoxide dismutase) level in gastric mucosa were also investigated as well as the influence of 5-HT (5-hydroxytryptamine) on gastric mucosal blood flow. Gastric mucosal blood flow was measured by the hydrogen gas clearance method. The vascular pattern of the stomach was investigated by the infusion method with two-colored silicon rubber. CoQ10 anion radical and SOD levels in gastric tissue were assayed by electron spin resonance (ESR) and radioimmunoassay. The gastric mucosal blood flow decreased significantly early after the induction of stress. Impairment of gastric mucosal blood flow was highly correlated with 5-HT and CoQ10 anion radical and SOD levels. Reduction in gastric mucosal blood flow was consequently due to opening of arteriovenular shunt and hyperpermeability of true capillaries influenced by 5-HT. These results demonstrate that ischemia and reperfusion after reduction of the gastric mucosal blood flow resulted in the sequence of events that led to formation of acute gastric mucosal lesions.
 ...
PMID:Gastric microcirculation and its regulating factors in stress. 194 Feb 4

A prior transient hindlimb ischemia/reperfusion (I/R) insult decreased acute lung injury in rats subsequently treated with cobra venom factor. I/R-mediated protection was associated with erythrocyte hemolysis, increased plasma catalase activity, and increased plasma hydrogen peroxide scavenging activity. In contrast, hindlimb I/R did not increase lung catalase activity, and large amounts of injected catalase were required to increase lung catalase activity. The results suggest that limited I/R in one organ can induce systemic processes that may decrease a subsequent O2 metabolite-mediated injury in another distant organ. The mechanism may involve release of catalase from hemolyzed erythrocytes at levels that are not sufficient to measurably increase total lung catalase activity.
 ...
PMID:Reperfusion of ischemic skeletal muscle causes erythrocyte hemolysis and decreases subsequent oxidant-mediated lung injury. 194 May 77

Superoxide radicals produced during acute intestinal ischemia are biochemically related with the presence of hydrogen peroxyde. In this study we have investigated the distribution of peroxidase-catalase activity, histochemically determined, in the ischemic ileal wall. In the rat, complete arterial and venous occlusion produced a progressive increase in extra-vascular peroxidase-catalase activity with a maximum corresponding to the ileal wall. Probably the tissue peroxidase-catalase activity is related to massive degranulation of polymorphonucleates.
 ...
PMID:Intestinal ischemia: morphological features--II. 196 11


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>