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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Induction of endothelial nitric oxide synthase (eNOS) contributes to the mechanism of heart protection against ischemia-reperfusion damage. We analyzed the effects of hypoxia and hyperoxia on eNOS expression in isolated working rat hearts after ischemia-reperfusion damage. Adult male Wistar rats were submitted to chronic hypoxia (2 weeks) and hyperoxia (72 h). The hearts were submitted to 15 min of ischemia and reperfused for 60 min, then we evaluated hemodynamic parameters and creatine phosphokinase (CPK) release. eNOS expression was estimated by RT-PCR; enzyme localization was evaluated by immunohistochemistry and the eNOS protein levels were detected by Western blot. All hemodynamic parameters in hypoxic conditions were better with respect to other groups. The CPK release was lower in hypoxic (P<0.01) than in normoxic and hyperoxic conditions. The eNOS deposition was significantly higher in the hypoxic group versus the normoxic or hyperoxic groups. The eNOS protein and mRNA levels were increased by hypoxia versus both other groups. Chronic hypoxic exposure may decrease injury and increase eNOS protein and mRNA levels in heart subjected to ischemia-reperfusion.
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PMID:Endothelial NOS expression and ischemia-reperfusion in isolated working rat heart from hypoxic and hyperoxic conditions. 1111 69

A number of surgical maneuvers require a period of liver ischemia. On reperfusion, hepatic injury results from a failure of the microcirculation and an excessive inflammatory response. Within the liver, sinusoidal cells produce a basal level of nitric oxide from endothelial nitric oxide synthase activity. During the early reperfusion period, increased concentrations of cytokines and oxygen free radicals result in expression of the inducible form of nitric oxide synthase, via activation of nuclear transcription factor-kappa B, in hepatocytes and Kupffer cells. This results in increased production of nitric oxide after 4 to 6 h from the onset of reperfusion. Nitric oxide generation attenuates the inflammatory response by counteracting endothelin, reducing inflammatory cell activity and decreasing the expression of cytokines and adhesion molecules. In animal models, therapeutic strategies that increase endogenous nitric oxide concentrations in the liver significantly decrease reperfusion injury. Such treatment modalities may have important clinical implications for the future, particularly in view of the increasing use in hepatic transplantation programs of marginal donor livers with their greater susceptibility to ischemia-reperfusion injury.
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PMID:Nitric oxide and hepatic ischemia-reperfusion injury. 1114 42

Oxidative stress may precondition the heart. The present study investigated whether hyperoxia elicits a preconditioning-like response. Rats were kept in a hyperoxic (>95% O2) environment for 60 or 180 minutes. Hearts were Langendorff-perfused immediately or 24 hours after hyperoxia, and exposed to 25 minutes of global ischemia and 60 minutes of reperfusion. Whole blood was sampled after 60 and 180 minutes of hyperoxia for oxidative stress markers. Hearts were sampled immediately or 24 hours after hyperoxia for measurement of antioxidants, lipid peroxidation products, heat shock protein 72 and endothelial nitric oxide synthase. At the end of reperfusion after 1 h hyperoxia, infarct size was determined by tetrazolium staining. Hyperoxia increased serum levels of conjugated dienes, reduced serum antioxidative protection, reduced reperfusion arrhythmias in most groups, and improved myocardial function. Infarct size was reduced from 45% of myocardial tissue in controls to 22% in treated animals. The myocardial activity of antioxidant enzymes, content of heat shock protein 72, and endothelial nitric oxide synthase in myocardial tissue were not influenced. In conclusion, hyperoxia induces a low-graded systemic oxidative stress, improves postischemic cardiac function and reduces infarct size. The mediators of protection remain to be determined.
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PMID:Pretreating rats with hyperoxia attenuates ischemia-reperfusion injury of the heart. 1126 75

Oxygen free radicals (OFR) play a primary role in ischemia-reperfusion-mediated vascular dysfunction and this is paralleled by a loss of endothelial nitric oxide synthase (eNOS) activity. The authors tested whether a direct exposure to OFR may affect vascular relaxation by altering nitric oxide (NO) release. Effects of electrolysis(EL)-generated OFR on basal and agonist-evoked NO release were monitored in isolated rat hearts by oxyhemoglobin assay. Electrolysis-induced changes were compared with those obtained after 30 min perfusion with NOS and cyclooxygenase (COX) inhibitors NG-nitro-L-arginine methyl ester (L-NAME, 100 microM) and indomethacin (INDO, 1 m M). Electrolysis-generated hydroxyl radical (.OH) formed by.O2-and H2O2 via the Fenton reaction as revealed by Electron Paramagnetic Resonance (EPR). After EL, basal NO release declined by 60% and coronary perfusion pressure (CPP) increased by approximately 70%. L-NAME/INDO perfusion similarly lowered NO release (-63%) but increased CPP less than EL (56+/-3%P<0.03 v post-EL). In presence of excess substrates and cofactors eNOS activity was not affected by EL. Both acetylcholine (ACh; 1 microM) and bradykinin (BK; 10 n M) had minimal effect in reversing EL-induced vasoconstriction, whereas both partially reversed L -NAME/INDO-mediated constriction. Sodium nitroprusside (SNP, 1 microM) completely reversed L-NAME/INDO constriction and partly countered that after EL (-38+/-2.5, P<0.001). Acetylcholine-evoked NO release was nearly abolished by both treatments whereas BK still elicited partial NO release after eNOS/cyclooxygenase inhibition (P<0.001) but not after EL. In conclusion, OFR severely impair NO-mediated coronary vasorelaxation affecting both basal and agonist-evoked NO release but not eNOS activity. However, EL also significantly blunts NOS/COX-independent vasodilation suggesting alteration of other vasodilatative pathways.
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PMID:Oxygen radical-mediated reduction in basal and agonist-evoked NO release in isolated rat heart. 1134 Dec 36

An electron microscopic immunocytochemical study was performed in order to determine the expression pattern of endothelial nitric oxide synthase (eNOS) in rat neurohypophysis after ischemia. In basal conditions eNOS was found to be weakly expressed on the endothelial cells and on single activated neurohypophyseal mastocytes. After cerebral ischemia, the number of mast cells increased in the neurohypophysis. The eNOS immunolabelling of mast cells was strongly enhanced between 10 min and 3 h after ischemia and declined at 24 h after ischemia. eNOS labelling was also enhanced in endotethelial cells between 30 min and 3 h after ischemia. Ultrastructurally, eNOS labelling was restricted to the granules of activated mast cells and the cytoplasm of endothelial cells. This study suggests that cerebral mastocytes are an important source of eNOS in neurohypophysis during ischemia and contribute to nitric oxide production in the perivascular space.
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PMID:Induction of endothelial nitric oxide synthase in perivascular mast cells in rat neurohypophysis after ischemia. 1146 13

Using immunoblot analysis and immunocytochemistry, we investigated expression and cellular localization of endothelial nitric oxide synthase (eNOS) and proliferating cell nuclear antigen (PCNA) in the l-arginine treated ischemic rat retina. In parallel, we tested whether the blood-retinal barrier was intact by immunocytochemistry using an antiserum against IgG. In the l-arginine-treated ischemic retina, the magnitude of the increased eNOS was higher, and PCNA was expressed in endothelial cells as well as in neurons in the inner retina during the whole experimental period. Finally, IgG leakage was not detectable in the l-arginine-treated ischemic retina. Our results clearly suggest that the increased NO production by eNOS may be essential for the survival of endothelial cells in the rat retina following transient ischemia.
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PMID:Up-regulated eNOS protects blood-retinal barrier in the L-arginine treated ischemic rat retina. 1149 19

The objective of this study was to investigate the effects of repeated, short-term ischemia on bradykinin-mediated permeability of the blood-brain barrier (BBB) and the blood-tumor barrier (BTB). The mechanism by which bradykinin transiently opens the BTB, involves B2 receptors, Ca2+ flux, nitric oxide (NO) and cyclic GMP (cGMP). Since global and focal cerebral ischemia are known to increase levels of brain nitric oxide synthase (bNOS) and endothelial nitric oxide synthase (eNOS) we tested the hypothesis that bradykinin may increase the BTB permeability to a greater extent under ischemic rather than nonischemic conditions. The vertebral arteries in female Wistar rats were coagulated immediately after intracerebral implantation of RG2 glioma. Short-term ischemia was produced in some rats by a modification of the four-vessel occlusion procedure for incomplete forebrain ischemia, in which the common carotid arteries were clamped daily for 15 min on days 7, 8 and 9 after tumor implantation, after which reperfusion was allowed. On day 10 after tumor implantation, bradykinin (10 microg kg(-1) min(-1)) or phosphate-buffered saline (PBS) was infused for 15 min into the right carotid artery of anesthetized, sham-operated (nonischemic controls) and ischemic rats, followed by an intravenous bolus (100 microCi kg(-1)) each of [14C]-iodo-antipyrine (IAP), [14C]-dextran or [14C]-aminoisobutyric acid (AIB) to measure regional cerebral blood flow (rCBF), blood volume, or unidirectional transfer constant Ki, respectively, by quantitative autoradiography. A single 15-min ischemic episode significantly decreased rCBF in the tumor center (158.9 +/- 17.33 in control vs. 58.78 +/- 24.45 ml 100 g(-1) min(-1) in ischemic group; p < 0.01) and in the tumor periphery (106.82 +/- 7.34 in control vs. 70.55 +/- 26.66 ml 100 g(-1) min(-1) in ischemic group; p < 0.05). Respective mean blood volume in tumors (11.7 +/- 13.3, 12.7 +/- 14.0, and 13.3 +/- 14.5 microl g(-1)) from ischemic-PBS, nonischemic-bradykinin, and ischemic-bradykinin groups, respectively, was not significantly different; mean blood volume in normal brain (3.7, 3.1 and 3.8 microl g(-1)) was not significantly different among these groups either. Intracarotid infusion of bradykinin following repeated ischemia significantly increased mean Ki, as compared to bradykinin infusion in nonischemic controls, in both the tumor center (36.60 +/- 8.4 vs. 22.90 +/- 4.61 microl g(-1) min(-1), p < 0.05) and in tumor periphery (17.70 +/- 5.93 vs. 8.50 +/- 4.42 microl g(-1) min(-1), p < 0.05). Mean Ki values for tumor center and tumor periphery of ischemic rats receiving intracarotid bradykinin were 3-fold greater than those of nonischemic rats infused with PBS. Immunohistochemical and Western blot analyses showed that repeated, short-term ischemia significantly increased the levels of bNOS in tumor cells and eNOS in tumor capillaries, but neither induced iNOS nor affected B2 receptor levels in tumor cells in vivo, as compared with nonischemic controls. Taken together, these results demonstrate for the first time that repeated, short-term ischemia augments bradykinin-mediated opening of the BTB. We conclude that the elevated intratumoral levels of bNOS and eNOS may 'prime' the NO generating capacity of tumor cells. Consequently, increased de novo synthesis and a correspondingly elevated concentration of NO within the tumor, therefore, may be one mechanistic explanation for the significantly increased, bradykinin-mediated BTB opening under ischemic conditions, reported here.
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PMID:Repeated, short-term ischemia augments bradykinin-mediated opening of the blood-tumor barrier in rats with RG2 glioma. 1154 33

Recent studies have suggested a proangiogenic effect of angiotensin-converting enzyme (ACE) inhibition. We hypothesized that such a proangiogenic effect of ACE inhibition may be mediated, in part, by bradykinin (BK) B(2)-receptor pathway. This study therefore examined the neovascularization induced by ACE inhibitor treatment in B(2) receptor-deficient mice (B(2)(-/-)) in a model of surgically induced hindlimb ischemia. After artery femoral occlusion, wild-type and B(2)(-/-) mice were treated with or without ACE inhibitor (perindopril, 3 mg/kg/d) for 28 days. Angiogenesis was then quantitated by microangiography, capillary density measurement, and laser Doppler perfusion imaging. The protein levels of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) were determined by Western blot. In wild-type animals, vessel density and capillary number in the ischemic leg were raised by 1.8- and 1.4-fold, respectively, in mice treated with ACE inhibitor when compared with the nontreated animals (P<0.01). This corresponded to an improved ischemic/nonischemic leg perfusion ratio by 1.5-fold in ACE inhibitor-treated animals when compared with the untreated ones (0.87+/-0.07 versus 0.59+/-0.05, respectively, P<0.01). Activation of the angiogenic process was also associated with a 1.7-fold increase in tissue eNOS protein level in mice treated with ACE inhibitor (P<0.05 versus control) but not with changes in VEGF protein level. Conversely, ACE inhibition did not affect vessel density, blood flow, and eNOS protein level in ischemic hindlimb of B(2)(-/-) mice. Therefore, proangiogenic effect of ACE inhibition is mediated by B(2)-receptor signaling and was associated with upregulation of eNOS content, independently of VEGF expression.
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PMID:Proangiogenic effect of angiotensin-converting enzyme inhibition is mediated by the bradykinin B(2) receptor pathway. 1159 90

Recent evidence has shown that the cardioprotection afforded by the late phase of ischemic preconditioning (PC) is mediated by upregulation of inducible nitric oxide synthase (iNOS). However, the specific cardiac cell type(s) that express(es) iNOS in response to ischemic PC remains unknown. Thus, mice underwent a sequence of six cycles of 4-min coronary occlusion/4-min reperfusion, which induces late PC, and tissue samples were collected at serial times for measurement of mRNA (Northern) and protein levels (Western). In addition, whole heart samples were cryosectioned for in situ hybridization and immunohistochemistry. The steady-state levels of iNOS mRNA in the ischemic regions started to increase at 1 h after ischemic PC, peaked at 3 h (201+/-31% of sham, n=5 P<0.01) and remained elevated at 24 h (177+/-22% of sham, n=5 P<0.01). In accordance with these data, iNOS protein expression was increased at 24 h (219+/-41% of sham, n=5 P<0.01). In contrast, neither endothelial nitric oxide synthase (eNOS) mRNA levels nor its protein expression changed at any time-point. The magnitude of iNOS upregulation after ischemic PC was mild compared with that noted 66 h after permanent coronary occlusion (360+/-53% of sham) or 8 h after endotoxin (3117+/-61% of control). After ischemic PC, diffuse iNOS signals were detected with in situ hybridization and immunohistochemistry in the cytoplasmic space of cardiac myocytes and, to a lesser degree, in the wall of large vessels, but were absent in smooth muscle and endothelium of small vessels and in fibroblasts. This pattern contrasted with that observed in mouse hearts subjected to permanent coronary occlusion where strong iNOS signals were concentrated in inflammatory cells but absent in cardiac myocytes. Thus, not only the degree of iNOS expression but also its cellular distribution were profoundly different in reversibly injured (preconditioned) v infarcted myocardium. We conclude that iNOS is rapidly upregulated after ischemic PC and that cardiac myocytes are the main source of ischemic PC-induced iNOS expression. This study demonstrates, for the first time, a differential pattern of iNOS expression in sublethal (PC) v lethal ischemia, which may have important implication for the role of iNOS in these two settings.
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PMID:Ischemic preconditioning upregulates inducible nitric oxide synthase in cardiac myocyte. 1181 60

Nitric oxide is produced from the amino acid L-arginine by nitric oxide synthase, which has three known isoforms: (1) endothelial nitric oxide synthase and (2) brain nitric oxide synthase, both of which are constitutive nitric oxide synthase; and (3) inducible nitric oxide synthase. The authors' hypothesis is that after reperfusion injury, endothelial cell dysfunction leads to disruption of nitric oxide synthase-mediated nitric oxide production and that this may in part explain the deleterious effects of ischemia-reperfusion injury on tissue survival and blood reflow in flaps. An experiment was designed to study the effects of ischemia-reperfusion injury on the bioactivity of all three isoforms of nitric oxide synthase. Buttock skin flaps and latissimus dorsi myocutaneous flaps were elevated in eight pigs. Flaps on one side of the animal were randomized to receive 6 hours of arterial ischemia, whereas flaps on the other side served as controls. At 6 hours of ischemia and at 1, 4, and 18 hours after reflow, tissue biopsy specimens were obtained and were processed for both constitutive nitric oxide synthase and inducible nitric oxide synthase enzyme activity on the basis of the L-citrulline assay. In addition, specimens were processed for Western blot analysis of the three isoforms. The authors' results revealed three key findings: first, there was a statistically significant (p < 0.001) decrease in constitutive nitric oxide synthase activity of ischemia-reperfusion-injured flaps as compared with controls in both skin and muscle for all time intervals measured. Second, Western blot analyses of endothelial nitric oxide synthase and brain nitric oxide synthase showed a significant decrease in the signal intensity in ischemic and reperfused tissue as compared with controls. Third, the inducible nitric oxide synthase isoform's activity and protein remained undetectable in both tissue types for all time points measured. The authors' data demonstrated that following ischemia-reperfusion injury in the pig flap model there was a disruption of constitutive nitric oxide synthase expression and activity, which may lead to decreased nitric oxide production. The significant decrease in nitric oxide synthase activity found in the current study may partly explain the mechanism of tissue damage in flaps subjected to ischemia-reperfusion injury. Knowledge of the kinetics of nitric oxide synthase activity under conditions of ischemia-reperfusion injury has important implications for the choice and timing of delivery of therapeutic agents whose goal is to increase the bioavailability of nitric oxide in reperfused tissue.
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PMID:Presence and activity of nitric oxide synthase isoforms in ischemia-reperfusion-injured flaps. 1193 8


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