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

Increased inducible nitric oxide synthase (iNOS) expression is a component of the immune response and has been demonstrated in cardiomyocytes in septic shock, myocarditis, transplant rejection, ischemia, and dilated cardiomyopathy. To explore whether the consequences of such expression are adaptive or pathogenic, we have generated a transgenic mouse model conditionally targeting the expression of a human iNOS cDNA to myocardium. Chronic cardiac-specific upregulation of iNOS in transgenic mice led to increased production of peroxynitrite. This was associated with a mild inflammatory cell infiltrate, cardiac fibrosis, hypertrophy, and dilatation. While iNOS-overexpressing mice infrequently developed overt heart failure, they displayed a high incidence of sudden cardiac death due to bradyarrhythmia. This dramatic cardiac phenotype was rescued by specific attenuation of transgene activity. These data implicate cardiomyocyte iNOS overexpression as sufficient to cause cardiomyopathy, bradyarrhythmia, and sudden cardiac death.
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PMID:Cardiomyocyte overexpression of iNOS in mice results in peroxynitrite generation, heart block, and sudden death. 1190 Nov 82

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

Activation of adenosine A(3) receptor (A(3)AR) protects against ischemia/reperfusion injury in the heart. However, the downstream signaling mechanisms leading to its delayed anti-ischemic effects remain unclear. We hypothesized that A(3)AR stimulation protects the heart via activation of nuclear transcription factor kappa B (NF-kappa B) and synthesis of inducible nitric oxide synthase (iNOS). Mice were treated with selective A(3)AR agonist, N(6)-(3-iodobenzyl) adenosine-5;-N-methyluronamide (IB-MECA). Twenty-four h later, hearts were perfused in Langendorff mode and subjected to 30 min of global ischemia and 30 min of reperfusion. IB-MECA caused post-ischemic reduction in necrosis and improvement in myocardial performance which was abolished by A(3)AR antagonist, MRS1191. Electrophoretic mobility shift assay demonstrated increased NF-kappa B binding in nuclear extracts following A(3)AR stimulation, which was diminished by MRS1191 and NF-kappa B inhibitor, pyrrolidinediethyldithiocarbamate (PDTC). The cardioprotection was abrogated by PDTC and targeted ablation of p50 subunit of NF-kappa B in mice. The inhibition of iNOS with S-methylisothiourea and targeted disruption of the iNOS gene also abolished the protective effect of A(3)AR stimulation. Expression of iNOS mRNA and NO production were enhanced after 6 and 24 h respectively of IB-MECA treatment. MRS1191 and PDTC blocked IB-MECA induced NO production after A(3)AR stimulation. MitoK(ATP) channel blocker, 5-hydroxydecanoate abolished the protective effect of A(3)AR. For the first time, we have provided direct evidence of an essential role of NF- kappa B activation and iNOS in A(3)AR-induced late preconditioning. Selective activation of A(3)AR with IB-MECA can be used to trigger long-lasting ischemic protection in the heart.
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PMID:Late preconditioning elicited by activation of adenosine A(3) receptor in heart: role of NF- kappa B, iNOS and mitochondrial K(ATP) channel. 1194 20

Ischemia reperfusion injury (IRI) model of rat heart was prepared by preperfusion for 15 min, then a suspension for 45 min and recycling reperfusion for 15 min with 30 ml KH buffer. The leakage of lactate dehydrogenase(LDH),protein, myoglobin and nitrite (NO2-) in the circular perfusion fluid were measured. Myocardial nitric oxide synthase(NOS) activity and L-arginine transport were observed. In the IR group, the leakage of LDH,protein, myoglobin and NO2- were increased respectively by 4.1,5.4,1 and 1.2 times(P<0.01) and NOS(tNOS, iNOS, cNOS) activity by 48.2%,43.2% and 52.1%,(P<0.01,respectively) as compared with the control group. L-arginine transport might be mediated by either high- or low-affinity transport system in cardiac tissue. In the IR group, L-arginine transport increased significantly with the V(max) being increased by 48% and 2 times respectively for the low-affinity and the high-affinity transport as compared with control. Michaelis constant (km) was decreased by 47.4% for low-affinity transport (P<0.05),but not significantly changed for the high-affinity transport. These results suggest that the increase of nitric oxide generation might result from the increased myocardial NOS activity and L-arginine transport during IRI.
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PMID:[Effects of myocardial ischemia reperfusion injury on L-arginine/nitric oxide system in rat heart]. 1197 71

Mild hypothermia is neuroprotective, but the reasons are not well known. Inflammation contributes to ischemic damage; therefore, we examined whether the protection by hypothermia may be attributable to alterations in the inflammation. We examined whether hypothermia might alter the inflammatory cell-associated inducible nitric oxide synthase (iNOS) and subsequent nitric oxide (NO) and peroxynitrite generation in experimental stroke and inflammation. Rats underwent 2 hr of middle cerebral artery occlusion (MCAO). Brain inflammation was modeled by intravenous lipopolysaccharide (LPS) (2 mg/kg) injection. Temperature was maintained at 33 degrees C for 2 hr immediately after MCAO and LPS injection, delayed 2 hr after MCAO or maintained at 38 degrees C. Cultured microglia were activated with LPS and then incubated at 33 or 37 degrees C. Both intraischemic and delayed mild hypothermia attenuated infarct size by 40% (p < 0.05). Immunohistochemistry was performed to identify cell type, iNOS, and peroxynitrite. The majority of iNOS- and peroxynitrite-positive cells were activated microglia-macrophages, and mild hypothermia significantly decreased the numbers of immunoreactive cells at 72 hr by >50% (p < 0.05). After ischemia, mild hypothermia decreased NO production by 40%. Similarly, hypothermia attenuated NO and iNOS in LPS-injected rats, as well as in cultured microglia. Aminoguanidine, an iNOS inhibitor, also attenuated infarct size and NO in ischemic and inflammation models. We conclude that mild hypothermia significantly inhibits the inflammatory response by affecting microglial iNOS-NO generation. Therapies directed against microglia or their activation may be useful in treating stroke.
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PMID:Influence of mild hypothermia on inducible nitric oxide synthase expression and reactive nitrogen production in experimental stroke and inflammation. 1201 11

Kupffer cells (KCs), the resident macrophages of the liver, contribute prominently to liver injury by inflammatory mediators. Pre-conditioning with the atrial natriuretic peptide (ANP), known also as a regulator of macrophage functions, attenuates hepatic ischemia-reperfusion injury. Therefore, the aim of this study was to determine the presence of functional ANP receptors on isolated KCs and to investigate whether this hepatoprotective hormone influences the activation of KCs. KCs were isolated by collagenase/pronase digestion followed by elutrial centrifugation and cultured for 1 to 3 days. Intracellular cyclic guanosine 3'5'-monophosphate (cGMP) concentrations were measured by radioimmunoassay after treating the cells with sodium nitroprusside or ANP. KCs were stimulated with bacterial lipopolysaccharide in the presence or absence of ANP, and inflammatory mediators were determined. Phagocytosis was assayed using Coumarin-labeled latex particles and flow cytometric analysis. Treatment of KCs with ANP but not with sodium nitroprusside resulted in a significant elevation of intracellular cGMP levels indicating functional type A natriuretic peptide receptors (NPR-As). ANP significantly reduced lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNFalpha) secretion, paralleled by an increased cell-associated TNFalpha. LPS-induced TNFalpha mRNA expression was not affected. ANP significantly increased phagocytotic activity of KCs via NPR-A. No effect of ANP on LPS-activated inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 protein levels, iNOS mRNA expression, nitric oxide, and PGE2-production was observed. We demonstrated functional cGMP-dependent ANP receptors in isolated rat KCs. ANP reduced TNFalpha release possibly by influencing post-translational processing of TNFalpha in LPS-activated KCs. In addition, we demonstrated that ANP enhances phagocytosis in KCs. These effects may contribute to the hepatoprotective actions of ANP.
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PMID:The atrial natriuretic peptide as a regulator of Kupffer cell functions. 1202 55

Chronic systemic hypoxia (SH) enhances myocardial ischemic tolerance in mammals. We studied the delayed cardioprotection caused by acute SH and associated signaling mechanism. Conscious adult male mice were exposed to one or two cycles of hypoxia (H; 10% O(2)) or normoxia (21% O(2)) for various durations (30 min, 2 h, 4 h) followed by 24 h of reoxygenation. Hearts were isolated 24 h later and subjected to ischemia-reperfusion in a Langendorff model. Infarct size was reduced in mice pretreated with one (H4h) or two cycles (H4hx2) of 4 h SH compared with normoxia mice (P < 0.05), which was abolished by an inducible nitric oxide synthase (NOS2) inhibitor (S-methylisothiourea, 3 mg/kg) given before SH or ischemia. H4hx2 also failed to reduce infarct size in NOS2 knockout mice. Cyclooxygenase-2 (COX-2) inhibitor (NS-398, 10 mg/kg) did not block the protection given either before H4hx2 or ischemia. A two- to three fold increase in myocardial NOS2 expression was observed in H4h, H2hx2, and H4hx2 (P < 0.05), whereas endothelial NOS (NOS3) or COX-2 remained unchanged. We conclude that acute SH induces delayed cardioprotection, which is triggered and mediated by NOS2, but not by NOS3 or COX-2.
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PMID:Evidence that NOS2 acts as a trigger and mediator of late preconditioning induced by acute systemic hypoxia. 1206 68

Protein kinase C (PKC) plays a central role in both early and late preconditioning (PC) but its association with inducible nitric oxide synthase (iNOS) is not clear in late PC. This study investigates the PKC signaling pathway in the late PC induced by activation of adenosine A(1) receptor (A(1)R) with adenosine agonist 2-chloro-N(6)-cyclopentyladenosine (CCPA) and the effect on iNOS upregulation. Adult male mice were pretreated with saline or CCPA (100 microg/kg iv) or CCPA (100 microg/kg iv) with PKC-delta inhibitor rottlerin (50 microg/kg ip). Twenty-four hours later, the hearts were isolated and perfused in the Langendorff mode. Hearts were subjected to 40 min of ischemia, followed by 30 min reperfusion. After ischemia, the left ventricular end-diastolic pressure (LVEDP) was significantly improved and the rate-pressure product (RPP) was significantly higher in the CCPA group compared with the ischemia-reperfusion (I/R) control group. Creatine kinase release and infarct size were significantly lower in the CCPA group compared with the I/R control group. These salutary effects of CCPA were abolished in hearts pretreated with rottlerin. Immunoblotting of PKC showed that PKC-delta was upregulated (150.0 +/- 11.4% of control group) whereas other PKC isoforms remained unchanged, and iNOS was also significantly increased (146.2 +/- 9.0%, P < 0.05 vs. control group) after 24 h of treatment with CCPA. The data show that PKC is an important component of PC with adenosine agonist. It is concluded that activation of A(1)R induces late PC via PKC-delta and iNOS signaling pathways.
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PMID:Adenosine A(1) receptor mediates late preconditioning via activation of PKC-delta signaling pathway. 1206 2

The onset of tissue ischemia is associated with significant changes in the expression of heparan sulfate- (HS) carrying core proteins that, in turn, lead to alterations in composition of the extracellular HS matrix. Since HS can bind numerous growth factors and cytokines, such changes in the HS matrix content can have profound effects on the ability of these factors to interact with their target cells. To investigate the role of increased HS matrix content on microvascular function, we used alpha-myosin heavy chain (MHC) promoter to overexpress a HS-carrying core protein, syndecan-4, in cardiac myocytes in mice. Mice expressing the transgene (alpha MHC-S4) demonstrated a significant increase in nitric oxide (NO) release in the coronary effluent in response to fibroblast growth factor 2 (FGF2, 1 microg/mL) administration despite similar expression levels of NO synthase genes II and III (iNOS and eNOS, respectively). In vitro studies of coronary microvessels derived from alpha MHC-S4 mice demonstrated increased relaxation response to FGF2 compared to control mice. At the same time, vasodilator response to adenosine diphosphate (ADP) was significantly impaired in alpha MHC-S4 mice-derived microvessels. Addition of exogenous HS to microvessels derived from control mice enhanced FGF2-induced vasodilation while inhibiting ADP-induced vasomotion. The vasomotor activity of the endothelial receptor-independent agent (A23187) and the endothelium-independent agent (sodium nitroprusside) was not affected by heparan sulfate. These results demonstrate that alterations in HS production have a profound and heterogeneous effect on endothelial receptor-dependent vasodilators and point to a novel role of the HS matrix in regulation of microvascular homeostasis.
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PMID:Modulation of microvascular signaling by heparan sulfate matrix: studies in syndecan-4 transgenic mice. 1207 29

This study was designed to investigate the effects of various chemically distinct activators of PPAR-gamma and PPAR-alpha in a rat model of acute myocardial infarction. Using Northern blot analysis and RT-PCR in samples of rat heart, we document the expression of the mRNA for PPAR-gamma (isoform 1 but not isoform 2) as well as PPAR-beta and PPAR-alpha in freshly isolated cardiac myocytes and cardiac fibroblasts and in the left and right ventricles of the heart. Using a rat model of regional myocardial ischemia and reperfusion (in vivo), we have discovered that various chemically distinct ligands of PPAR-gamma (including the TZDs rosiglitazone, ciglitazone, and pioglitazone, as well as the cyclopentanone prostaglandins 15D-PGJ2 and PGA1) cause a substantial reduction of myocardial infarct size in the rat. We demonstrate that two distinct ligands of PPAR-alpha (including clofibrate and WY 14643) also cause a substantial reduction of myocardial infarct size in the rat. The most pronounced reduction in infarct size was observed with the endogenous PPAR-gamma ligand, 15-deoxyDelta12,14-prostagalndin J2 (15D-PGJ2). The mechanisms of the cardioprotective effects of 15D-PGJ2 may include 1) activation of PPAR-alpha, 2) activation of PPAR-gamma, 3) expression of HO-1, and 4) inhibition of the activation of NF-kappaB in the ischemic-reperfused heart. Inhibition by 15D-PGJ2 of the activation of NF-kappaB in turn results in a reduction of the 1) expression of inducible nitric oxide synthase and the nitration of proteins by peroxynitrite, 2) formation of the chemokine MCP-1, and 3) expression of the adhesion molecule ICAM-1. We speculate that ligands of PPAR-gamma and PPAR-alpha may be useful in the therapy of conditions associated with ischemia-reperfusion of the heart and other organs. Our findings also imply that TZDs and fibrates may help protect the heart against ischemia-reperfusion injury. This beneficial effect of 15D-PGJ2 was associated with a reduction in the expression of the 1) adhesion molecules ICAM-1 and P-selectin, 2) chemokine macrophage chemotactic protein 1, and 3) inducible isoform of nitric oxide synthase. 15D-PGJ2 reduced the nitration of proteins (immunohistological analysis of nitrotyrosine formation) caused by ischemia-reperfusion, likely due to the generation of peroxynitrite. Not all of the effects of 15D-PGJ2, however, are due to the activation of PPAR-gamma. For instance, exposure of rat cardiac myocytes to 15D-PGJ2, but not to rosiglitazone, results in an up-regulation of the expression of the mRNA for heme-oxygenase-1 (HO-1). Taken together, these results provide convincing evidence that several, chemically distinct ligands of PPAR-gamma reduce the tissue necrosis associated with acute myocardial infarction.
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PMID:Ligands of the peroxisome proliferator-activated receptors (PPAR-gamma and PPAR-alpha) reduce myocardial infarct size. 1208 64


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