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

Research on the biochemistry and physiology of l-arginine has remained an attractive area for scientists over the last 100 years due to its diverse physiological functions in mammals. Research on l-arginine was boosted after the identification of nitric oxide (NO) and agmatine and their physiological importance. NO directly modulates ion channels, activates soluble guanylyl cyclase and other important proteins by ADP ribosylation and nitrosylation and binding to heme or iron-sulfur clusters. These modifications and interaction with heme might activate or inhibit various protein kinases, phosphatases and modulate transcription of various nuclear factors to possibly cause cardiovascular diseases like hypertension, ischemia, diabetes, atherosclerosis and angiogenesis. Agmatine holds the key to prevent the toxic effects associated with induction of NO synthesis by its ability to inhibit inducible nitric oxide synthase (iNOS). Agmatine is also synthesized from l-arginine by the enzyme arginine decarboxylase and displays a significant potential in cardiovascular system. Agmatine, with the myriad of effects on calcium homeostasis, seems to modulate various functions in the heart, brain and vasculature. The present review compiles the recent development to improve the understanding the role played by l-arginine-metabolic pathways in cardiovascular system. Though l-arginine and its metabolites are well known to affect various cardiovascular physiologies, the currently available literature is still not sufficient to validate the prophylactic/therapeutic efficacy of l-arginine. l-Arginine and its metabolites, NO and agmatine still hold the key for future research in cardiovascular system.
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PMID:Vascular regulation by the L-arginine metabolites, nitric oxide and agmatine. 1499 49

The cardioprotective actions of nitric oxide (NO) have largely been attributed to cGMP. NO may, however, elicit some biological actions independently of cGMP. We tested the hypothesis that the NO donor sodium nitroprusside specifically protects isolated cardiomyocytes from injury at least in part independently of its ability to elevate cGMP by using metabolic inhibition to simulate ischemia. Metabolic inhibition-induced injury of adult rat cardiomyocytes (increased activity of lactate dehydrogenase and creatine kinase) was significantly reduced by sodium nitroprusside by at least 30% at all concentrations studied (0.3-100 microM). Sodium nitroprusside (1 microM) increased cardiomyocyte cGMP content, but neither a stable analogue of cGMP (8-bromo-cGMP) nor a potent cGMP stimulus (atrial natriuretic peptide) mimicked the protective effects of sodium nitroprusside. Moreover, inhibition of soluble guanylyl cyclase failed to inhibit sodium nitroprusside cardiomyocyte protection. Conversely, inhibition of either ATP-sensitive potassium (K(ATP)) channels with glibenclamide (10 microM) or calcium-sensitive potassium (K(Ca)) channels with tetraethylammonium bromide (1 mM) or iberiotoxin (20 nM) markedly attenuated the cardioprotective actions of sodium nitroprusside. In conclusion, sodium nitroprusside protects isolated cardiomyocytes from metabolic inhibition independently of cGMP; rather, inhibition of K(Ca) and K(ATP) channels reverses the sodium nitroprusside actions, thus unmasking another mechanism for NO-mediated protection in cardiomyocytes.
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PMID:Sodium nitroprusside protects adult rat cardiac myocytes from cellular injury induced by simulated ischemia: role for a non-cGMP-dependent mechanism of nitric oxide protection. 1642 79

We investigated whether atrial natriuretic peptide (ANP) given just prior to reperfusion reduces infarction in rabbit hearts and whether protection is related to activation of protein kinase G (PKG). Isolated rabbit hearts were subjected to a 30-min period of regional ischemia; treated hearts received a 20-min infusion of ANP (0.1 microM) starting 5 min before 2 h of reperfusion. ANP infusion decreased infarction from 31.5+/-2.4% of the risk zone in untreated hearts to 12.5+/-2.0% (P<0.001). To explore mechanisms of protection ischemic hearts were treated simultaneously with ANP and isatin, a blocker of the natriuretic peptide receptor, shortly before reperfusion. ANP's protective effect was aborted (36.8+/-2.9% infarction). There is no acceptable blocker of protein kinase G that can be used in intact organs. However, 8-(4-chlorophenylthio)-guanosine 3', 5'-cyclic monophosphate (10 microM), a cell-permeable cGMP analog that directly activates PKG, was infused from 5 min before to 15 min after reperfusion. The PKG activator mimicked ANP's protection with only 18.2+/-3.6% infarction (P<0.001). 5-Hydroxyde-canoate (5-HD), a putative mitochondrial KATP channel (mKATP) inhibitor, abrogated ANP's protection (34.4+/-2.6% infarction). Unexpectedly, 1H-[1,2,4]oxadiazole- [4,3-a]quinoxalin-1-one (ODQ), a blocker of soluble guanylyl cyclase also prevented ANP's infarct-sparing effect. It is unclear whether this observation implicated participation of soluble guanylyl cyclase in the mechanism or simply a lack of selectivity of ODQ. Finally the reperfusion injury salvage kinases (RISK), phosphatidylinositol 3-kinase and extracellular signal-regulated kinase, were implicated in ANP's mechanism since either wortmannin or PD98059 infused at reperfusion prevented ANP's infarct-sparing effect. ANP administered just prior to reperfusion protects hearts against infarction, likely by activation of PKG, opening of mKATP, and stimulation of downstream kinases.
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PMID:Atrial natriuretic peptide administered just prior to reperfusion limits infarction in rabbit hearts. 1660 40

Carbon monoxide (CO), a byproduct of heme catalysis, was shown to have potent cytoprotective and anti-inflammatory effects. In vivo recipient CO inhalation at low concentrations prevented ischemia/reperfusion (I/R) injury associated with small intestinal transplantation (SITx). This study examined whether ex vivo delivery of CO in University of Wisconsin (UW) solution could ameliorate intestinal I/R injury. Orthotopic syngenic SITx was performed in Lewis rats after 6 h cold preservation in control UW or UW that was bubbled with CO gas (0.1-5%) (CO-UW). Recipient survival with intestinal grafts preserved in 5%, but not 0.1%, CO-UW improved to 86.7% (13/15) from 53% (9/17) with control UW. At 3 h after SITx, grafts stored in 5% CO-UW showed improved intestinal barrier function, less mucosal denudation and reduced inflammatory mediator upregulation compared to those in control UW. Preservation in CO-UW associated with reduced vascular resistance (end preservation), increased graft cyclic guanosine monophosphate levels (1 h), and improved graft blood flow (1 h). Protective effects of CO-UW were reversed by ODQ, an inhibitor of soluble guanylyl cyclase. In vitro culture experiment also showed better preservation of vascular endothelial cells with CO-UW. The study suggests that ex vivo CO delivery into UW solution would be a simple and innovative therapeutic strategy to prevent transplant-induced I/R injury.
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PMID:Ex vivo application of carbon monoxide in University of Wisconsin solution to prevent intestinal cold ischemia/reperfusion injury. 1682 83

Previous studies have shown that endothelial nitric oxide (NO) synthase (eNOS)-derived NO is an important signaling molecule in ischemia-reperfusion (I-R) injury. Deficiency of eNOS-derived NO has been shown to exacerbate injury in hepatic and myocardial models of I-R. We hypothesized that transgenic overexpression of eNOS (eNOS-TG) would reduce hepatic I-R injury. We subjected two strains of eNOS-TG mice to 45 min of hepatic ischemia and 5 h of reperfusion. Both strains were protected from hepatic I-R injury compared with wild-type littermates. Because the mechanism for this protection is still unclear, additional studies were performed by using inhibitors and activators of both soluble guanylyl cyclase (sGC) and heme oxygenase-1 (HO-1) enzymes. Blocking sGC with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and HO-1 with zinc (III) deuteroporphyrin IX-2,4-bisethyleneglycol (ZnDPBG) in wild-type mice increased hepatic I-R injury, whereas pharmacologically activating these enzymes significantly attenuated I-R injury in wild-type mice. Interestingly, ODQ abolished the protective effects of eNOS overexpression, whereas ZnDPBG had no effect. These results suggest that hepatic protection in eNOS-TG mice may be mediated in part by NO signaling via the sGC-cGMP pathway and is independent of HO-1 signal transduction pathways.
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PMID:Genetic overexpression of eNOS attenuates hepatic ischemia-reperfusion injury. 1687 50

Taurine has been thought to be essential for the development and survival of neural cells and to protect them under cell-damaging conditions. In the brain stem taurine regulates many vital functions, including cardiovascular control and arterial blood pressure. We have recently characterized the release of taurine in the adult and developing brain stem under normal conditions. Now we studied the properties of preloaded [3H]taurine release under various cell-damaging conditions (hypoxia, hypoglycemia, ischemia, the presence of metabolic poisons and free radicals) in slices prepared from the mouse brain stem from developing (7-day-old) and young adult (3-month-old) mice, using a superfusion system. Taurine release was greatly enhanced under these cell-damaging conditions, the only exception being the presence of free radicals in both age groups. The ischemia-induced release was characterized to consist of both Ca2+-dependent and -independent components. Moreover, the release was mediated by Na+-, Cl--dependent transporters operating outwards, particularly in the immature brain stem. Cl- channel antagonists reduced the release at both ages, indicating that a part of the release occurs through ion channels, and protein kinase C appeared to be involved. The release was also modulated by cyclic GMP second messenger systems, since inhibitors of soluble guanylyl cyclase and phosphodiesterases suppressed ischemic taurine release. The inhibition of phospholipases also reduced taurine release at both ages. This ischemia-induced taurine release could constitute an important mechanism against excitotoxicity, protecting the brain stem under cell-damaging conditions.
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PMID:Taurine release in mouse brain stem slices under cell-damaging conditions. 1699 16

Preconditioning the heart by exposure to brief cycles of ischemia-reperfusion causes it to become very resistant to ischemia-induced infarction. This protection has been shown to depend on a large number of signal transduction components whose arrangements within the cardiomyocyte are unknown. To aid the translation of this phenomenon to the clinical setting, we have attempted to map the signal transduction pathways responsible for this protection. To resolve the signaling order we have injected a signal at an intermediate point in the system transduction pathway and monitored it at a downstream site. System analysis reveals both parallel and series signaling arrangements. Separate trigger and mediator phases could be identified. The trigger phase is now well mapped. During the preconditioning ischemia, autacoids--including adenosine, opioids, and bradykinin--are released from the heart. These substances occupy their respective Gi-coupled receptors. Opioid and bradykinin receptors activate phosphatidylinositol 3-kinase (PI3-kinase) which, through phosphoinositide-dependent protein kinase, causes activation of Akt. Opioid couples through transactivation of the epidermal growth factor receptor, while bradykinin's coupling to PI3-kinase is unknown. PI3-kinase causes extracellular signal regulated kinase (ERK)-dependent activation of endothelial nitric oxide synthase. The resulting nitric oxide activates soluble guanylyl cyclase resulting in cyclic C-GMP-dependent protein kinase (PKG) activation through production of cyclic guanosine monophosphate. PKG initiates opening of ATP-sensitive potassium channels on the inner membrane of the mitochondria. Potassium entry into mitochondria causes the generation of free radicals during reperfusion when oxygen is reintroduced. Through redox signaling, these radicals activate protein kinase C (PKC) and put the heart into the protected phenotype that persists for one to two hours. Although adenosine receptors activate PI3-kinase, they also have a second direct coupling to PKC and thus bypass the mitochondrial pathway. The mediator phase occurs during the first minutes of reperfusion following the lethal ischemic insult and is still poorly defined. Briefly, PKC somehow potentiates adenosine's ability to activate signaling from low-affinity A(2b) adenosine receptors. These receptors couple to the survival kinases, Akt and ERK, believed to inhibit the formation of deadly mitochondrial permeability transition pores through the phosphorylation of glycogen synthase kinase-3beta. The proposed signaling maps reveal many points at which drugs can trigger the protected phenotype.
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PMID:Mapping preconditioning's signaling pathways: an engineering approach. 1837 91

Increased hemichannel opening induced by oxygen glucose deprivation (OGD) was reported in the hippocampal pyramidal neuron. It was suggested that the pannexin1 hemichannel opening could mediate ionic flux dysregulation, anoxic depolarization, and energy-depleting efflux of glucose and ATP for ischemic neurons. However, the regulatory mechanisms of pannexin1 hemichannel opening have been poorly understood. Here we showed that excessive generation of nitric oxide (NO) during ischemia could induce the calcein leakage from neurons, which was markedly reduced by NO synthase inhibitor. The calcein leakage from neurons during OGD was also attenuated by the application of N-ethylmaleimide (NEM), an SH-alkylating agent, and dithiothreitol (DTT), a reducer of oxidized sulfhydryl groups. However, the soluble guanylyl cyclase (sGC) inhibitor had a minor effect on the calcein leakage during OGD. Furthermore, the elevated intracellular but not extracellular levels of glutathione could also inhibit the calcein leakage during OGD. Similar results were observed in metabolic inhibition (MI), which is another ischemic-like condition. Finally, immunocytochemical and immunoblotting analysis revealed that, after 1 hr of OGD stimulation, the distribution and expression of pannexin1 showed no significant difference compared with control. However, the pannexin1 mRNA expression was elevated after 1 hr of OGD and a sustained increase was maintained during reperfusion. These results implied that the reactive oxygen species (ROS), especially NO, might be involved in the enhanced pannexin1 hemichannel opening and that the S-nitrosylation but not the NO/cGMP pathway played a more important role in this event.
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PMID:Role for nitric oxide in permeability of hippocampal neuronal hemichannels during oxygen glucose deprivation. 1838 63

The protective effects of nitric oxide (NO), a physiological activator of soluble guanylyl cyclase (sGC), have been reported in ischemia-reperfusion (I/R) syndrome of the lung. Therefore, we studied the effects of BAY 41-2272, a novel sGC stimulator, on I/R injury of the lung in an isolated intact organ model. Lung injury was assessed by measuring weight gain and microvascular permeability (capillary filtration coefficient, K(fc)). Release of reactive oxygen species (ROS) into the perfusate was measured during early reperfusion by electron spin resonance (ESR) spectroscopy. Rabbit lungs were treated with BAY 41-2272, N(G)-monomethyl-L-arginine (L-NMMA), or NO to evaluate the effects on I/R-induced lung injury. In untreated lungs, a dramatic rise in K(fc) values and weight gain during reperfusion were observed, and these results were associated with increased ROS production. Both, BAY 41-2272 and L-NMMA significantly attenuated vascular leakage and suppressed ROS release. Additional experiments showed that BAY 41-2272 diminished PMA-induced ROS production by NADPH oxidase. A pharmacological inhibition of the enzyme with consequent reduction in ROS levels decreased I/R injury. NO had only marginal effect on I/R injury. Thus BAY 41-2272 protects against I/R-induced lung injury by interfering with the activation of NADPH oxidases.
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PMID:Novel soluble guanylyl cyclase stimulator BAY 41-2272 attenuates ischemia-reperfusion-induced lung injury. 1907 57

The aim of this study was to investigate the role of endothelial nitric oxide synthase (eNOS) in the host myocardium on bone marrow mesenchymal stromal cells (MSC) migration to the ischemic myocardium and whether stromal cell-derived factor-1alpha (SDF-1alpha) contributes to eNOS-mediated MSC migration. MSCs and coronary microvascular endothelial cells were isolated from adult wild-type (WT) mouse bone marrow and hearts, respectively. Cultured neonatal cardiomyocytes from WT, eNOS(-/-), and eNOS overexpressing transgenic (Tg) mice were subjected to anoxia and reoxygenation (A/R), and the conditioned medium was used as a chemoattractant for in vitro transendothelial migration assay. MSC migration was decreased in the presence of conditioned medium derived from eNOS(-/-) cardiomyocytes but increased in the presence of eNOS-Tg conditioned medium. SDF-1alpha expression was decreased in eNOS(-/-) but increased in eNOS-Tg cardiomyocytes following A/R and in the myocardium following ischemia/reperfusion (I/R). SDF-1alpha expression was cGMP-dependent as inhibition of soluble guanylyl cyclase decreased SDF-1alpha expression in WT cardiomyocytes. MSCs expressed very low levels of eNOS proteins compared with the adult myocardium. To examine MSC migration in vivo, MSCs derived from mice expressing enhanced green fluorescence protein (EGFP(+)) were intravenously administered to WT mice subjected to myocardial I/R. EGFP(+) cells in the ischemic region were decreased in eNOS(-/-) but increased in eNOS-Tg compared with WT hearts. MSC treatment improved cardiac function following I/R in WT but not in eNOS(-/-) mice. In conclusion, eNOS in the host myocardium promotes MSC migration to the ischemic myocardium and improves cardiac function through cGMP-dependent increases in SDF-1alpha expression.
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PMID:Endothelial nitric oxide synthase promotes bone marrow stromal cell migration to the ischemic myocardium via upregulation of stromal cell-derived factor-1alpha. 1935 24


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