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)

Inhibition of angiotensin II AT1 receptors protects against stroke, reducing the cerebral blood flow decrease in the periphery of the ischemic lesion. To clarify the mechanism, spontaneously hypertensive rats (SHR) and normotensive control Wistar Kyoto (WKY) rats were pretreated with the AT1 receptor antagonist candesartan (0.3 mg. kg.(-1) d(-1)) for 28 days, a treatment identical to that which protected SHR from brain ischemia, and the authors studied middle cerebral artery (MCA) and common carotid morphology, endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) messenger RNA (mRNA), and protein expression in cerebral microvessels, principal arteries of the Willis polygon, and common carotid artery. The MCA and common carotid artery of SHR exhibited inward eutrophic remodeling, with decreased lumen diameter and increased media thickness when compared with WKY rats. In addition, there was decreased eNOS and increased iNOS protein and mRNA in common carotid artery, circle of Willis, and brain microvessels of SHR when compared with WKY rats. Both remodeling and alterations in eNOS and iNOS expression in SHR were completely reversed by long-term AT1 receptor inhibition. The hemodynamic, morphologic, and biochemical alterations in hypertension associated with increased vulnerability to brain ischemia are fully reversed by AT1 receptor blockade, indicating that AT1 receptor activation is crucial for the maintenance of the pathologic alterations in cerebrovascular circulation during hypertension, and that their blockade may be of therapeutic advantage.
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PMID:Normalization of endothelial and inducible nitric oxide synthase expression in brain microvessels of spontaneously hypertensive rats by angiotensin II AT1 receptor inhibition. 1262 12

Patterns of endothelial nitric oxide synthase (eNOS) expression in retinal ischemia were studied utilizing a transient high intraocular pressure (HIOP) model. We investigated neuronal cell damage and changes in eNOS immunoreactive expression in the ischemic retina, and its relationship to the neuroprotection of betaxolol treatment after ischemic injury. Immunohistochemical staining for eNOS was performed at 3, 7, 14 and 28 days after ischemia/reperfusion. In controls, eNOS immunoreactivity was detected in retinal vessels, but was not detected in neurons. After ischemia/reperfusion, the intensity of eNOS immunoreactivity increased in both retinal vessels and the ganglion cell layer (GCL) compared with controls. eNOS-positive neurons were induced first in the inner nuclear layer (INL) 7 days after reperfusion. However, when experiments were carried out on animals that had been treated with betaxolol after ischemia/reperfusion, the intensity of eNOS immunoreactivity decreased compared to the untreated ischemic retinas. These results suggest that an increase in eNOS expression could be associated with the degenerative changes in the ischemic retina, and that betaxolol treatment appears to protect retinal tissue from ischemic damage.
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PMID:Change in endothelial nitric oxide synthase in the rat retina following transient ischemia. 1263 78

The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been shown to upregulate endothelial nitric oxide synthase in isolated endothelial cells in a manner that is independent of their lipid-lowering effects. Nitric oxide inhibits polymorphonuclear leukocyte (PMN) adherence and attenuates cardiac dysfunction caused by PMNs after ischemia/reperfusion. Therefore, the authors hypothesized that a new statin, rosuvastatin, could attenuate PMN-induced cardiac dysfunction, and examined the effects of rosuvastatin in isolated ischemic (20 min) and reperfused (45 min) rat hearts perfused with PMNs. Rosuvastatin (0.25 or 1.25 mg/kg) given 18 h before ischemia/reperfusion significantly improved left ventricular developed pressure (P < 0.01) and the maximal rate of development of left ventricular developed pressure (+dP/dt(max), P < 0.01) compared with ischemia/reperfused hearts obtained from rats given 0.9% NaCl. The time point for the improved cardiac performance caused by rosuvastatin (1.25 mg/kg) was 20 min after reperfusion. In addition, rosuvastatin significantly reduced PMN adherence to the vascular endothelium and subsequent infiltration into the postischemic myocardium (P < 0.01). The nitric oxide synthase inhibitor N omega-nitro-l-arginine methyl ester (50 micromol/l) blocked these cardioprotective effects. These results provide evidence that rosuvastatin significantly attenuates PMN-induced cardiac contractile dysfunction in the isolated perfused rat heart.
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PMID:Rosuvastatin, a new HMG-CoA reductase inhibitor, protects ischemic reperfused myocardium in normocholesterolemic rats. 1265 68

Ischemia-induced angiogenic response is reduced in spontaneously hypertensive rats (SHR). To study whether exogenous basic fibroblast growth factor (bFGF) infusion is effective in expanding collateral circulation in frankly hypertensive SHR, femoral arteries of male SHR (weighing approximately 250 g) were kept intact (nonoccluded control; n = 9) or occluded for 4h(n = 12) or for 16 days with vehicle (n = 14) or bFGF [0.5 (n = 17), 5.0 (n = 13), and 50.0 (n = 14) microg. kg-1. day-1 for 14 days] intraarterially. Maximal collateral-dependent blood flows (BF) to the hindlimbs were determined with 85Sr- and 141Ce-labeled microspheres during running at 20 and 25 m/min (15% grade). Preexercise heart rates (approximately 530 beats/min) and blood pressures (BP; approximately 200 mmHg) were similar across groups except in the high-dose bFGF group, where BP was reduced by approximately 12% (P < 0.05). Femoral artery occlusion for 4 h resulted in approximately 95% reduction of BF in calf muscles [199 +/- 18.7 (nonoccluded group) to 10 +/- 1.0 ml. min-1. 100 g-1; P < 0.001]. BF to calf muscles of the vehicle and low-dose bFGF (0.5 microg. kg-1. day-1) groups increased to 36 +/- 3.2 and 45 +/- 2.0 ml. min-1. 100 g-1, respectively (P < 0.001). bFGF infusion at 5.0 and 50.0 microg. kg-1. day-1 further increased (P < 0.001) BF to calf muscles (62 +/- 4.6 and 62 +/- 2.2 ml. min-1. 100 g-1, respectively). Our results show that bFGF can effectively increase BF in hypertensive rats. The reduced hypertension with high-dose bFGF suggests that a critical signal in arteriogenesis (nitric oxide bioavailability) may be restored. These findings suggest that the dulled endothelial nitric oxide synthase of SHR does not preempt collateral vessel remodeling.
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PMID:Basic fibroblast growth factor increases collateral blood flow in spontaneously hypertensive rats. 1276 49

Expression of adrenomedullin, discovered as a vasodilatory peptide, is markedly up-regulated under pathological conditions such as tissue ischemia and inflammation, which are associated with neovascularization. Here, we tested the hypothesis that overly expressed adrenomedullin may augment collateral flow to ischemic tissues. We induced hindlimb ischemia in wild-type mice and injected a naked plasmid expressing human adrenomedullin or an empty vector into the ischemic muscle, followed by in vivo electroporation. Adrenomedullin markedly enhanced blood flow recovery as determined by Laser Doppler imaging. The mice treated with an empty vector suffered frequent autoamputation of the ischemic toe, which was completely prevented by adrenomedullin. Anti-CD31 immunostaining revealed that adrenomedullin significantly increased capillary density. The angiogenic effect of adrenomedullin was abrogated in endothelial nitric oxide synthase (eNOS)-deficient mice. These results indicate that adrenomedullin may promote collateral growth in response to ischemia through activation of eNOS.
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PMID:Adrenomedullin augments collateral development in response to acute ischemia. 1278 59

In liver resection and transplantation ischemia-reperfusion injury (IRI) is one of the main causes of organ dys- or nonfunction. The aim of the present study was to determine whether alpha-lipoic acid (LA) is able to attenuate IRI. Rat livers were perfused with Krebs-Henseleit buffer with or without LA (+/-wortmannin), followed by ischemia (1 h, 37 degrees C) and reperfusion (90 min). Efflux of lactate dehydrogenase (LDH) and purine nucleoside phosphorylase (PNP) and hepatic ATP content were determined enzymatically. Activation of NF-kappaB and activating protein 1 (AP-1) was examined by EMSA, and protein phosphorylation was examined by Western blot. Caspase-3-like activity served as an indicator for apoptotic processes. Animals treated intravenously with 500 micromol LA were subjected to 90 min of partial no-flow ischemia followed by reperfusion for up to 7 days. Preconditioning with LA significantly reduced LDH and PNP efflux during reperfusion in isolated perfused rat livers. ATP content was significantly increased in LA-treated livers. Postischemic activation of NF-kappaB and AP-1 was significantly reduced in LA-pretreated organs. Preconditioning with LA significantly enhanced Akt phosphorylation. It showed neither effect on endothelial nitric oxide synthase nor on Bad phosphorylation. Importantly, simultaneous administration of wortmannin, an inhibitor of the phosphatidylinositol (PI)3-kinase/Akt pathway, blocked the protective effect of LA on IRI, demonstrating a causal relationship between Akt activation and hepatoprotection by LA. Interestingly, despite activation of Akt, LA did not reduce postischemic apoptotic cell death. The efficacy of LA treatment in vivo was shown by reduced GST plasma levels and improved liver histology of animals pretreated with LA. This study shows for the first time that the PI3-kinase/Akt pathway plays a central protective role in IRI of the rat liver and that LA administration attenuates IRI via this pathway.
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PMID:Alpha-lipoic acid preconditioning reduces ischemia-reperfusion injury of the rat liver via the PI3-kinase/Akt pathway. 1281 56

Previous studies have suggested that the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors attenuate ischemia-reperfusion injury by increasing the activity of endothelial nitric oxide synthase (eNOS). We assessed whether short-term treatment with atorvastatin reduces myocardial infarct size in the rat. Rats (male Sprague-Dawley) received atorvastatin 2 mg/kg per day (n = 9), 10 mg/kg per day (n = 8), or 75 mg/kg per day (n = 11), or placebo (n = 11) by gastric gavage for 3 days. Two additional groups received atorvastatin 10 mg/kg (n = 7) or placebo (n = 7) for 3 days and the nonselective nitric oxide synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), 15 mg/kg intravenously 15 min before surgery. All rats underwent 30 min of coronary artery occlusion followed by 180 min of reperfusion. Ischemic myocardium at risk was assessed with blue dye and infarct size by triphenyltetrazolium chloride. Ischemic myocardium at risk was comparable among groups. Infarct size, expressed as a percentage of the myocardium at risk, was significantly smaller in the atorvastatin 75 mg/kg group (22.6 +/- 2.8%; p = 0.035 vs. placebo) and atorvastatin 10 mg/kg (20.3 +/- 3.8%; p = 0.022 vs. placebo) compared with placebo (37.5 +/- 4.3%). The effect of atorvastatin 2 mg/kg was of smaller magnitude and did not reach statistical significance (infarct size 30.6 +/- 4.2% of the myocardium at risk). L-NAME abolished the protective effect of atorvastatin 10 mg/kg per day. Infarct size was 43.0 +/- 4.1% in the atorvastatin group and 39.4 +/- 3.3% in the placebo group (p = 0.503). In conclusion, short-term (3 days) atorvastatin (10-75 mg/kg/d) significantly reduced myocardial infarct size. The protective effect was completely abolished by L-NAME, strongly suggesting that this protective effect is mediated via the nitric oxide synthase pathway.
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PMID:Reduction of infarct size by short-term pretreatment with atorvastatin. 1284 84

The activity of endothelial nitric oxide synthase (eNOS) is subject to complex transcriptional and post-translational regulation including the association with several proteins and variations in subcellular distribution. In the present study we describe a transgenic mouse model expressing eNOS fused to green fluorescent protein (GFP), which allows the study of localization and regulation of eNOS expression. We tested the functionality of eNOS in the eNOS-GFP mice. Expression of eNOS was restricted to the endothelial lining of blood vessels in various tissues tested, without appreciable expression in non-endothelial cells. Activity of the enzyme was confirmed by assaying the conversion of L-arginine to L-citrulline. NO production in isolated vessels was increased in transgenic mice when compared to non-transgenic control animals (4.88 +/- 0.59 and 2.48 +/- 0.47 micro mol/L NO, respectively, P < 0.005). Both the mean aortic pressure and the pulmonary artery pressure were reduced in eNOS-GFP mice (both approximately 30%, P < 0.05). Plasma cholesterol levels were also slightly reduced ( approximately 20%, P < 0.05). In conclusion, eNOS-GFP mice express functional eNOS and provide a unique model to study regulation of eNOS activity or eNOS-mediated vascular events, including response to ischemia, response to differences in shear stress, angiogenesis and vasculogenesis, and to study the subcellular distribution in relation with functional responses to these events.
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PMID:Functional expression of endothelial nitric oxide synthase fused to green fluorescent protein in transgenic mice. 1450 74

Chronic hypoxia may precondition the myocardium and protect from ischemia-reperfusion damage. We therefore examined the recovery of left and right ventricular function after ischemia and reperfusion (15 min each) in isolated blood-perfused working hearts from normoxic (Norm) and hypoxic (Hypo; 14 days, 10.5% O(2)) adult rats. In addition, the mRNA expression of hypoxia-inducible factor (HIF)-1alpha and the protein expression of endothelial nitric oxide synthase (eNOS) were measured. Postischemic left ventricular function recovered to 66 +/- 6% and 67 +/- 5% of baseline in Norm and Hypo, respectively. In contrast, postischemic right ventricular function was 93 +/- 2% of baseline in Hypo vs. 67 +/- 3% in Norm (P < 0.05). Improved postischemic right ventricular function in Hypo (93 +/- 2% and 96 +/- 2% of baseline) was observed with 95% O(2) or 21% O(2) in the perfusate, and it was not attenuated by glibenclamide (5 and 10 micromol/l) (86 +/- 4% and 106 +/- 6% recovery). HIF-1alpha mRNA and eNOS protein expression were increased in both left and right hypoxic ventricles. In conclusion, postischemic right, but not left, ventricular function was improved by preceding chronic hypoxia. ATP-sensitive K(+) channels are not responsible for the increased right ventricular tolerance to ischemia after chronic hypoxia in adult rat hearts.
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PMID:Responses of chronically hypoxic rat hearts to ischemia: KATP channel blockade does not abolish increased RV tolerance to ischemia. 1455 Oct 60

Subthreshold excitotoxic stimuli such as brief cerebral ischemia or chemically induced seizures modulate brain injury resulting from subsequent transient ischemia. Depending on the delay between the two insults, either tolerance or cumulative damage will develop. We were interested whether non-chemically induced inherent epileptic seizures as they occur in Mongolian gerbils have an effect on the outcome of a transient global ischemia, i.e., whether they are an interfering variable in ischemia experiments. Occurrence of spontaneous seizures in adult male gerbils was registered with a video-controlled seizure monitoring system. Bilateral occlusion of common carotid arteries was carried out 2 h or 24 h after the last generalized seizure. After 4 days survival, the extent of ischemia-induced neuronal damage and glial activation were assessed in the hippocampus and striatum. No significant difference in the ischemia induced nerve cell loss was observed in cresyl violet stained sections between the 2-h or 24-h interval gerbils. Neuronal expression of endothelial nitric oxide synthase in CA1 disappeared with neuronal degeneration. Distribution and degree of upregulation of glial fibrillary acidic protein as marker for astrocytes did not differ between the two groups. We concluded that non-chemically induced inherent epileptic seizures neither protect the gerbil brain from injury nor augment the degree of damage resulting from transient forebrain ischemia. Thus, inherent epileptic seizures do not influence the outcome of the insult, making the gerbil a reliable model for studies on transient brain ischemia.
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PMID:Effect of inherent epileptic seizures on brain injury after transient cerebral ischemia in Mongolian gerbils. 1455 6


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