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

Increased release of endothelium-derived relaxing factor/nitric oxide has been proposed as the final common pathway for vasodilator responses to gram-negative lipopolysaccharide (endotoxin). To test this hypothesis, we examined endothelium-dependent and endothelium-independent vasodilator agents in vascular smooth muscle isolated from guinea pigs 16 hours after injection of saline (control group) or induction of Escherichia coli endotoxemia; aortic rings (approximately 1 mm in diameter) were studied with standard isometric tension techniques. Endotoxemia resulted in a significant loss of vasodilator responses to the endothelium-dependent receptor agonists acetylcholine (10(-10)-10(-5) M) and ADP (10(-8)-10(-5) M). In contrast, endotoxemia did not affect vasodilator responses to either the endothelium-dependent receptor agonist substance P (10(-11)-10(-7) M), the endothelium-dependent and receptor-independent agonist A23187 (10(-9)-10(-6) M), or the endothelium-independent agonist nitroprusside (10(-10)-10(-4) M). The nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) inhibited the vasodilator response to acetylcholine more in vessels from lipopolysaccharide-injected than control guinea pigs. Unexpectedly, L-NAME converted the endothelium-dependent vasodilator action of ADP to an endothelium-dependent vasoconstrictor response that was blocked individually by the cyclooxygenase inhibitor indomethacin, the thromboxane synthase inhibitor dazoxiben, and the thromboxane A2 receptor antagonist SQ29548. We conclude that in vivo endotoxemia inhibits the constitutive isoform of nitric oxide synthase in endothelial cells by selectively disrupting receptor-coupled activation mechanisms shared by acetylcholine and ADP. Furthermore, since L-NAME unmasks a thromboxane A2-mediated vasoconstrictor action of the endogenous purinoceptor agonist ADP, drugs that inhibit nitric oxide synthase could exacerbate sepsis-induced vasoconstriction and ischemia by synergizing with lipopolysaccharide-induced inhibition of endothelial nitric oxide synthase.
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PMID:Selective inhibition of endothelium-dependent vasodilator capacity by Escherichia coli endotoxemia. 767 34

Although the importance of injury with consequent activation of endothelium is well-recognized in diseases affecting the glomerular endothelial cell (GEN), research on GEN injury in vivo has been hampered by the lack of adequate animal models. Here we report the establishment and characterization of a new GEN injury model in rats. This model was induced by selective renal artery perfusion with anti-GEN IgG and resulted in the severe acute renal failure with marked platelet deposition and development of a thrombotic microangiopathy involving glomeruli. Peritubular capillary endothelial cells were also damaged that was associated with severe tubular necrosis. Although the glomerular changes were severe, half of the glomeruli recovered by day 10, while interstitial changes remained throughout our observation time course. Proliferation of GEN was observed during the recovery phase. An increased expression of endothelial nitric oxide synthase in GEN was also observed, and may be an adaptive mechanism to counteract the thrombosis and ischemia. This model should be useful to investigate the pathophysiology of renal microvascular diseases and the mechanisms of GEN injury, activation and recovery in vivo.
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PMID:A new model of renal microvascular endothelial injury. 921 61

Recovery of the brain after a period of cerebral ischemia depends greatly on the restoration of nutritive blood flow, which, however, may be severely disturbed. Early post-ischemic deficits (no-reflow) multiply with increasing duration of ischemia. The pathophysiology is multifactorial and includes vascular factors (endothelial blebs, compression by swollen glial cells), blood factors (viscosity changes due to erythrocyte sludging, platelet aggregation, blood dehydration), and general cardiovascular factors (post-ischemic hypotension, venous congestion). Treatment of no-reflow requires a combination therapy (e.g., hypertensive flush, small volume hypertonic solutions, fibrinolysis) for interfering with as many of these factors as possible. Delayed post-ischemic hypoperfusion develops after a preceding phase of post-ischemic hyperemia and is characterized by increased vasotonus. Hypoperfusion is associated with a disturbed coupling between brain function, metabolism, and blood flow, and may lead to secondary stimulation of anaerobic metabolism. Causal factors include disturbed blood/vessel wall interactions (expression of adhesion molecules, generation of free radicals) and possibly down-regulation of endothelial nitric oxide synthase. Treatment of post-ischemic hypoperfusion includes neutrophil elimination and free radical scavengers but is still unsatisfactory. Improvement of reperfusion deficits is a challenging task that must be solved before proceeding to specific molecular interventions for the treatment of ischemic cell injury.
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PMID:Reperfusion of the brain after global ischemia: hemodynamic disturbances. 926 98

Aging is associated with a progressive decline in renal function and the development of glomerulosclerosis and interstitial fibrosis. Although many studies have addressed the cellular mechanisms of age-related glomerulosclerosis, less is known about the tubulointerstitial fibrosis. In this study, aging (24 mo) rats develop tubulointerstitial fibrosis characterized by tubular injury and focal tubular cell proliferation, myofibroblast activation, macrophage infiltration with increased immunostaining for the adhesive proteins osteopontin and intercellular adhesion molecule-1, and collagen IV deposition. Aging rats demonstrated immunostaining for endothelial nitric oxide synthase (eNOSIII) in renal tubular epithelial cells and infiltrating mononuclear cells in areas of tubulointerstitial injury, with a relative loss of staining of the peritubular capillaries compared with young rats. The aging rats also displayed focal loss of peritubular capillaries (as noted by focally decreased RECA-1 and OX-2 staining) in areas of tubulointerstitial injury. The areas of fibrosis and hypocellularity were associated with increased apoptosis of tubular and interstitial cells compared with young (3 mo) rats (25.4 +/- 5.3 versus 3.5 +/- 2.5 TUNEL-positive cells/0.25 mm2 in old versus young rats, P = 0.0001). It is concluded that tubulointerstitial fibrosis in aging is an active process associated with interstitial inflammation and fibroblast activation. The progressive loss of cells in areas of fibrosis may be due to accelerated apoptosis. Furthermore, the tubulointerstitial injury may be the consequence of ischemia secondary to peritubular capillary injury and altered eNOS expression.
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PMID:Tubulointerstitial disease in aging: evidence for underlying peritubular capillary damage, a potential role for renal ischemia. 952 99

Electron microscopy immunocytochemical study was performed to clarify ultrastructural localization and role of endothelial nitric oxide synthase (EC-NOS) in the endothelial cells (EC) of rat hippocampal vessels after transient cerebral ischemia. EC-NOS immunoreactivity was found in the endothelial cells in association with plasma membrane, sub-plasmalemmal vesicles, basal membrane and in cytosol (cytoplasm free of subcellular organelles). A sharp transient increase in immunoreactivity of NOS was observed at 10 min up to 1 hour after ischemia. The results of the present study indicate that NO, as a potent vasodilator, may play a protective role in ischemic brain damage.
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PMID:Endothelial nitric oxide synthase in vascular endothelium of rat hippocampus after ischemia: evidence and significance. 959 52

We tested the hypothesis that endothelial nitric oxide synthase (eNOS) modulates angiogenesis in two animal models in which therapeutic angiogenesis has been characterized as a compensatory response to tissue ischemia. We first administered L-arginine, previously shown to augment endogenous production of NO, to normal rabbits with operatively induced hindlimb ischemia. Angiogenesis in the ischemic hindlimb was significantly improved by dietary supplementation with L-arginine, compared to placebo-treated controls; angiographically evident vascularity in the ischemic limb, hemodynamic indices of limb perfusion, capillary density, and vasomotor reactivity in the collateral vessel-dependent ischemic limb were all improved by oral L-arginine supplementation. A murine model of operatively induced hindlimb ischemia was used to investigate the impact of targeted disruption of the gene encoding for ENOS on angiogenesis. Angiogenesis in the ischemic hindlimb was significantly impaired in eNOS-/- mice versus wild-type controls evaluated by either laser Doppler flow analysis or capillary density measurement. Impaired angiogenesis in eNOS-/- mice was not improved by administration of vascular endothelial growth factor (VEGF), suggesting that eNOS acts downstream from VEGF. Thus, (a) eNOS is a downstream mediator for in vivo angiogenesis, and (b) promoting eNOS activity by L-arginine supplementation accelerates in vivo angiogenesis. These findings suggest that defective endothelial NO synthesis may limit angiogenesis in patients with endothelial dysfunction related to atherosclerosis, and that oral L-arginine supplementation constitutes a potential therapeutic strategy for accelerating angiogenesis in patients with advanced vascular obstruction.
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PMID:Nitric oxide synthase modulates angiogenesis in response to tissue ischemia. 961 28

Reactive oxygen species (ROS) are produced in ischemia and reperfusion. Since endothelial nitric oxide synthase (eNOS) is key to the endothelium-dependent vasodilation, we examined the effects of peroxide on this enzyme. We treated cells cultured from pig coronary artery endothelium with different concentrations of hydrogen peroxide, washed them, solubilized them and measured NOS activity by arginine to citrulline conversion. Hydrogen peroxide inhibited the eNOS activity with an IC50 value of 0.85 +/- 0.39 mM. In another experiment, we perfused arteries with solutions containing 0 or 1 mM hydrogen peroxide, washed them, removed the endothelium using a cotton swab, centrifuged and solubilized the endothelium and monitored its NOS activity. Hydrogen peroxide (1 mM) did not affect the NOS activity significantly (p > 0.05) in this assay. We conclude that the inactivation of eNOS by hydrogen peroxide does not play a major role in the ischemia-reperfusion damage because the peroxide concentrations attained during ischemia-perfusion are much lower than those affecting the eNOS activity.
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PMID:Effects of peroxide on endothelial nitric oxide synthase in coronary arteries. 965 89

The recent advances in the histopathology of ischemia have set forth new proposals, particularly in regard to excitotoxicity by the glutamate receptor, NMDA. The participation of the nitric oxide (NO) in normal and pathological conditions and its relationship with toxicity in ischemia, suggest new alternatives for the modulation of the NMDA receptor REDOX site through its pharmacologic manipulation. This event would potentially limit the consequences of the activation-calcium flow and the production of peroxoinitrite during the ischemic phenomenon. The present work delivers two proposals: 1) A modified technique to the ones that have been described, of endovascular, without craniectomy, for experimental cerebral ischemia in Wistar rats, and with particular harmful effect upon the hippocampus. 2) It promotes the use of nitrates as an additional alternative to other elements, in order to restrict excitotoxicity in the described experimental cerebral ischemia, and paying attention to CA1-CA2 of the hippocampus. This area, specially sensitive to hypoxia-ischemia, offers an excellent study option for focal, experimental, cerebral ischemia associated with toxicity mediated by excitatory amino acids, since it stores an important concentration of NMDA receptors (R1/R2 A) as well as endothelial nitric oxide synthase. Our parameters are supported by quantitative-qualitative cell analysis, and not by the extension of the stroke which offers a more objective perspective upon the assessment of the focal ischemic event. By means of this technique, these results confirm the extent of the ischemic injury to the cell at the level of the hippocampus compared to a control/basal group, P = 0.0006. Furthermore, it suggests a neuroprotective effect of isosorbide dinitrate since it preserves the viable cells, and limits the appearance of hypoxic-ischemic cells at the hippocampus when the middle cerebral artery (MCA) is occluded endovascularly, as compared to the animals with no treatment P = 0.0080. However, other research lines are needed to compare the efficacy of this present work with other therapeutic proposals.
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PMID:Neuroprotection in selective focal ischemia in rats by nitrates, an alternative redox manipulation on nitric oxide: experimental model. 980 40

Targeted disruption of the neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS) genes has led to knockout mice that lack these isoforms. These animal models have been useful to study the roles of nitric oxide (NO) in physiologic processes. nNOS knockout mice have enlarged stomachs and defects in the inhibitory junction potential involved in gastrointestinal motility. eNOS knockout mice are hypertensive and lack endothelium-derived relaxing factor activity. When these animals are subjected to models of focal ischemia, the nNOS mutant mice develop smaller infarcts, consistent with a role for nNOS in neurotoxicity following cerebral ischemia. In contrast, eNOS mutant mice develop larger infarcts, and show a more pronounced hemodynamic effect of vascular occlusion. The knockout mice also show that nNOS and eNOS isoforms differentially modulate the release of neurotransmitters in various regions of the brain. eNOS knockout mice respond to vessel injury with greater neointimal proliferation, confirming that reduced NO levels seen in endothelial dysfunction change the vessel response to injury. Furthermore, eNOS mutant mice still show a protective effect of female gender, indicating that the mechanism of this protection cannot be limited to upregulation of eNOS expression. The eNOS mutant mice also prove that eNOS modulates the cardiac contractile response to ss-adrenergic agonists and baseline diastolic relaxation. Atrial natriuretic peptide, upregulated in the hearts of eNOS mutant mice, normalizes cGMP levels and restores normal diastolic relaxation.
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PMID:Neuronal and endothelial nitric oxide synthase gene knockout mice. 1055 36

The aim of this work was to investigate in the rat the protective effect of an oral administration (one week) of Panax ginseng (PG) extract (10 mg/ml in drinking water; 1.6 g/kg/day) on myocardial post-ischemic damage induced by hyperbaric oxygen (HBO) and on the loss in functionality of the endothelium in aorta ring preparations. The hearts from control rats (no-HBO and no-HBO-PG), and from rats exposed to HBO and to HBO after PG treatment were isolated and subjected to mild ischemia and then reperfused. HBO greatly worsens the post-ischemic damage in controls, as demonstrated by the rise of left ventricular end diastolic pressure (LVEDP) and coronary perfusion pressure (CPP). PG significantly restrained the increase of LVEDP and CPP in respect to HBO-untreated rats, as well as that of CPP induced by injection of angiotensin II during pre-ischemia. In HBO control rats the reduction of the vasorelaxant effect of acetylcholine on norepinephrine precontracted aortic rings, was markedly recovered by PG; a similar trend was observed in aortic rings challenged with the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (56% recovery). These results strongly indicate that PG prevents the myocardial ischemia/reperfusion damage and the impairment of endothelial functionality induced by reactive oxygen species arising from HBO exposure, through an antioxidant intervention. The in vitro radical scavenging activity of PG seems to be too weak (0.05-0.5 mg/ml) to explain by itself the cardiac and extra-cardiac protective effects, and this suggests a role also for an indirect antioxidant action of the drug (endothelial nitric oxide synthase stimulation).
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PMID:Panax ginseng administration in the rat prevents myocardial ischemia-reperfusion damage induced by hyperbaric oxygen: evidence for an antioxidant intervention. 1057 76


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