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)

To elucidate the details of tryptase release from the heart during ischemia-reperfusion (I/R), we attempted the enzymatic measurement of tryptase release from the isolated guinea pig heart perfused by the Langendorff mode I/R model. Tryptase-like activity in the effluent was monitored by the hydrolysis of L-Pyr-Gly-Arg-MCA. Tryptase-like protease and histamine were rapidly released from heart during ischemia within 10 min. After reperfusion, tryptase-like protease levels decreased, achieving stabilization. The tryptase-like protease activity in the effluent was inactivated by serine protease inhibitors. The pattern of inhibition was similar to those of guinea pig and human lung tryptase. In conclusion, tryptase was released into the coronary effluent during ischemia, but not during reperfusion in guinea pig heart.
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PMID:Enzymatic measurement of tryptase-like protease release from isolated perfused guinea pig heart during ischemia-reperfusion. 1627 8

Glycine reduces ischemia-reperfusion injury after experimental liver transplantation. We hypothesized that glycine might also protect right heart function in an isovolumic cardiac transplantation model. In six domestic donor pigs 150 ml of a 300 mmol L-glycine solution were administered intravenously. The hearts were then arrested with histidine-tryptophan-ketoglutarate solution. Animals without prior glycine infusion served as controls (n = 6). After 4 h of ischemia, hearts were transplanted into recipients. An isovolumic model was used in which the right ventricular (RV) volume was controlled in vivo using an intracavitary high-compliance balloon. After 1 and 2 h of reperfusion the RV balloon volume was gradually increased and the developed pressures were recorded (P(developed) = P(systolic) - P(diastolic)). Right ventricular failure was defined as a decrease in developed intracavitary pressure. Glycine hearts could be loaded with a significantly increased volume after 1 h (glycine: 53 +/- 13.7 ml vs. control: 32 +/- 11.7 ml; P = 0.015) and after 2 h (67 +/- 18.6 ml vs. 43 +/- 8.2 ml; P = 0.018). Maximal RV developed pressures were not significantly different between groups. Postischemic RV end-diastolic compliance was significantly higher in glycine-treated animals (P = 0.04). Glycine protects early postischemic RV compliance, but has no important influence on maximal developed pressures.
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PMID:Glycine application and right heart function in a porcine heart transplantation model. 1644 71

Radiolabeled alpha(v)beta(3)-integrin antagonists are increasingly investigated as a means of imaging angiogenesis. Several methods of labeling alpha(v)beta(3)-integrin binding peptide with (18)F have been reported recently. In the present study, we devised a straightforward means for labeling Arg-Gly-Asp (RGD) peptide with (18)F via hydrazone formation between c(RGDyK)-hydrazinonicotinic acid (HYNIC) (3) and 4-[(18)F]-fluorobenzaldehyde ([(18)F]4). The resulting reaction mixture was purified by HPLC to give 4'-[(18)F]-fluorobenzylidenehydrazone-6-nicotinamide-c(RGDyK) ([(18)F]5). The conjugation efficiency of 3 and 4 to form [(18)F]5 was 95.2%, and the radiochemical purity of [(18)F]5 after purification was >99%. The specific activity of [(18)F]5 estimated by radio-HPLC was 20.5 GBq/mumol (end of synthesis). Competitive binding assay of c(RGDyK) (1) and 5 was performed using [(125)I]iodo-c(RGDyK) as a radioligand, and K(i) values were found to be 2.8 and 21.7 nM, respectively. For the biodistribution study, the angiogenic mouse model was established by inducing unilateral ischemia on the left hindlimbs of ICR mice after femoral artery ablation. Seven days after inducing ischemia, [(18)F]5 was administered to the mice through the tail vein. Ischemic muscle uptake of [(18)F]5 was significantly higher than that of normal muscle (P<.01). Specific uptake was confirmed by coinjection of 1 with [(18)F]5. Here, we successfully labeled RGD peptide with (18)F via hydrazone formation between 3 and 4, resulting to [(18)F]5. [(18)F]5 was found to have high affinity for alpha(v)beta(3)-integrin and to accumulate specifically in ischemic hindlimb muscle of mice. We suggest that (18)F labeling via formation of hydrazone between HYNIC peptide and [(18)F]4 is a useful method for labeling c(RGDyK), which can be applied for imaging angiogenesis.
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PMID:An improved method of 18F peptide labeling: hydrazone formation with HYNIC-conjugated c(RGDyK). 1684 43

Acute renal failure (ARF) induces tubular hyperresponsiveness to TLR4 ligands, culminating in exaggerated renal cytokine/chemokine production. However, the fate of TLR4 protein during acute tubular injury remains unknown. The study sought new insights into this issue. Male CD-1 mice were subjected to 1) unilateral ischemia-reperfusion (I/R), 2) cisplatin (CP) nephrotoxicity, or 3) glycerol-induced myohemoglobinuric ARF. Renal cortical TLR4 protein (Western blotting, immunohistochemistry) and TLR4 mRNA levels (RT-PCR) were determined thereafter (90 min-4 days). Urinary TLR4 excretion post-I/R or CP injection was also assessed. To gain proximal tubule-specific results, TLR4 protein and mRNA were quantified in posthypoxic or oxidant (Fe)-challenged isolated mouse tubules. Finally, TLR4 mRNA was determined in antimycin A-injured cultured proximal tubular (HK-2) cells. Acute in vivo renal injury reduced proximal tubule TLR4 content. These changes corresponded with the appearance of TLR4 fragment(s) in urine and a persistent increase in renal cortical TLR4 mRNA. Isolated proximal tubules responded to injury with rapid TLR4 reductions, dramatic extracellular TLR4 release, and increases in TLR4 mRNA. Glycine blocked these processes, implying membrane pore formation was involved. HK-2 cell injury increased TLR4 mRNA, but not protein levels, suggesting intact transcriptional, but not translational, pathways. Diverse forms of acute tubular injury rapidly reduce proximal tubular TLR4 content. Plasma membrane TLR4 release through glycine-suppressible pores, possibly coupled with a translation block, appears to be involved. Rapid postinjury urinary TLR4 excretion suggests its potential utility as a "biomarker" of impending ARF.
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PMID:Toll-like receptor (TLR4) shedding and depletion: acute proximal tubular cell responses to hypoxic and toxic injury. 1688 50

Glycine is a non-essential amino acid which is cheap, easily available and relatively non-toxic. It is composed of a single carbon attached to an amino and a carboxyl group, with a molecular weight of 75. It is involved in the production of bile, nucleic acids, porphyrins and creatine phosphate. It is part of the normal human diet and is used clinically, as an irrigant solution in urological and gynaecological procedures. Glycine has broad spectrum anti-inflammatory, cytoprotective and immunomodulatory properties whose therapeutic role has largely been un-investigated. Since the demonstration of its cytoprotective effect on hypoxic cultured renal tubule cells, further research has established its mechanism of anti-inflammatory action, which depends on stimulation of glycine sensitive chloride channel receptors on the cell membrane. The mechanism of non-specific cytoprotective effect which is present even in chloride and calcium free media is not clear. However glycine is currently being used experimentally, in human liver transplant recipients and has been shown to be beneficial in animal models of ischemia-reperfusion injury (IRI) in liver and several other organs. This review addresses the properties of glycine, its mechanism of action and its role in modulating IRI with special reference to the liver, with the aim of stimulating translational research into the potential role of glycine as a pharmaceutical agent.
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PMID:The role of glycine in hepatic ischemia-reperfusion injury. 1691 24

Ischemic heart disease in diabetic patients might be linked to the accumulation of advanced-glycation end products (AGEs). In ischemic rat hearts, expression of receptor for AGEs and its ligands is significantly enhanced and involved in cardiac ischemia/reperfusion (I/R) injury even in the absence of diabetes. It has recently been reported that diabetic human myocardium cannot be protected by preconditioning. In this context, our hypothesis was that beta1-adrenergic preconditioning might be altered in the presence of AGEs. Using an isolated non-working rat heart model, this study investigated the effect of AGEs on cardioprotection induced by transient beta1-adrenoceptor (beta1-AR) stimulation with xamoterol (Xa). After 6-hydroxydopamine (6-OHDA) pre-treatment and a 20-min stabilization period, hearts were perfused at constant pressure for 20 min, then subjected to 40 min of global ischemia and 30 min of reperfusion (I/R, Ctrl); and exposed to 0.01 microm Xa for 5 min framed with or without 15.2 microm albumin (Alb) or glycated albumin (Gly Alb). The main endpoints were the mean coronary flow (MCF), the left ventricular end-diastolic pressure (LVEDP), rate-pressure product (RPP) and creatine kinase (CK) release and necrosis area. XA induced an increase in the MCF after I/R (t = 85 min), a protective effect on the LVEDP, an improvement in RPP, a decrease of CK release during reperfusion and a reduction of necrotic area. The beneficial effects induced by Xa during reperfusion were suppressed by the administration of Gly Alb during Xa infusion, whereas Alb did not hamper Xa-induced protection. These results suggest that AGEs suppress the cardioprotection resulting from the activation of beta1-ARs and thus might contribute to cardiovascular damages seen in diabetic patients.
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PMID:Advanced-glycation end products (AGEs) derived from glycated albumin suppress early beta1-adrenergic preconditioning. 1722 43

The Na+/Ca2+ exchanger (NCX) is an ion transporter that exchanges Na+ and Ca2+ in either Ca2+-efflux or Ca2+-influx mode, depending on membrane potential and transmembrane ion gradients. In myocytes, neurons, and renal tubular cells, NCX is thought to play an important role in the regulation of intracellular Ca2+ concentration. So far the benzyloxyphenyl derivatives (KB-R7943, SEA0400, SN-6, and YM-244769) have been developed as selective NCX inhibitors. These inhibitors possess different isoform selectivities, although they have similar properties, such as Ca2+-influx mode selectivity and I1 inactivation-dependence. Site-directed mutageneses have revealed that these inhibitors possess some molecular determinants (Phe-213, Val-227, Tyr-228, Gly-833, and Asn-839) for interaction with NCX1. These benzyloxyphenyl derivatives are expected to be useful tools to study the physiological roles of NCX. Interestingly, benzyloxyphenyl NCX inhibitors effectively prevent several ischemia-reperfusion injuries and salt-dependent hypertension in animal models. Furthermore, several experiments with genetically engineered mice provide compelling evidence that these diseases are triggered by pathological Ca2+ entry through NCX1. Thus, NCX inhibitors may have therapeutic potential as novel drugs for reperfusion injury and salt-dependent hypertension.
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PMID:Na+/Ca2+ exchange as a drug target--insights from molecular pharmacology and genetic engineering. 1744 96

Glycine 2-methyl proline glutamate (G-2mPE) is a proline-modified analogue to the naturally existing N-terminal tripeptide glycine-proline-glutamate that is a cleaved product from insulin-like growth factor-1. G-2mPE is designed to be more enzymatically resistant than glycine-proline-glutamate and to increase its bioavailability. The current study has investigated the protective effects of G-2mPE following hypoxic-ischemic brain injury in the neonatal brain. On postnatal day 7, Wistar rats were exposed to hypoxia-ischemia (HI). HI was induced by unilateral ligation of the left carotid artery followed by hypoxia (7.7% O2, 36 degrees C) for 60 min. The drug treatment started 2 h after the insult, and the pups were given either 1.2 mg/kg (bolus), 1.2 mg/ml once a day for 7 days, or vehicle. The degree of brain damage was determined histochemically by thionin/acid fuchsin staining. G-2mPE's anti-inflammatory properties were investigated by IL-1beta, IL-6, and IL-18 ELISA, and effects on apoptosis by caspase 3 activity. Vascularization was determined immunohistochemically by the total length of isolectin-positive blood vessels. Effect on astrocytosis was also determined in the hippocampus. Animals treated with multiple doses of G-2mPE demonstrated reduced overall brain injury 7 days after HI, particularly in the hippocampus and thalamus compared to vehicle-treated rats. The expression of IL-6 was decreased in G-2mPE-treated animals compared to vehicle-treated pups, and both the capillary length and astrogliosis were increased in the drug-treated animals. There was no effect on caspase 3 activity. This study indicates that peripheral administration of G-2mPE, starting 2 h after a hypoxic-ischemic insult, reduces the degree of brain injury in the immature rat brain. The normalization of IL-6 levels and the promotion of both neovascularization and reactive astrocytosis may be potential mechanisms that underlie its protective effects.
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PMID:Delayed peripheral administration of a GPE analogue induces astrogliosis and angiogenesis and reduces inflammation and brain injury following hypoxia-ischemia in the neonatal rat. 1776 7

Adult neural stem and progenitor cells (NSPCs) are important autologous transplantation tools in regenerative medicine, as they can secrete factors that protect the ischemic brain. We investigated whether adult NSPCs genetically modified to secrete more glial cell line-derived neurotrophic factor (GDNF) could protect against transient ischemia in rats. NSPCs were harvested from the subventricular zone of adult Wistar rats and cultured for 3 weeks in the presence of epidermal growth factor. The NSPCs were treated with fibre-mutant Arg-Gly-Asp adenovirus containing the GDNF gene (NSPC-GDNF) or enhanced green fluorescent protein (EGFP) gene (NSPC-EGFP; control group). In one experiment, cultured cells were transplanted into the right ischemic boundary zone of Wistar rat brains. One week later, animals underwent 90 min of intraluminal right middle cerebral artery occlusion followed by magnetic resonance imaging and behavioural tests. The NSPC-GDNF group had higher behavioural scores and lesser infarct volume than did controls at 1, 7 and 28 days postocclusion. In the second experiment, we transplanted NSPCs 3 h after ischemic insult. Compared to controls, rats receiving NSPC-GDNF had decreased infarct volume and better behavioural assessments at 7 days post-transplant. Animals were killed on day 7 and brains were collected for GDNF ELISA and morphological assessment. Compared to controls, more GDNF was secreted, more NSPC-GDNF cells migrated toward the ischemic core and more NSPC-GDNF cells expressed immature neuronal marker. Moreover, the NSPC-GDNF group showed more effective inhibition of microglial invasion and apoptosis. These findings suggest that NSPC-GDNF may be useful in treatment of cerebral ischemia.
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PMID:Adult neural stem and progenitor cells modified to secrete GDNF can protect, migrate and integrate after intracerebral transplantation in rats with transient forebrain ischemia. 1788 Mar 88

A number of Lys-Pro-containing short peptides have been described as possessing a variety of biological activities in vitro. Because of limited metabolic stability, however, their efficacy in vivo is uncertain. To exploit the pharmacological potential of Lys-Pro-containing short peptides, we synthesized a series of chemically modified forms of these peptides. One of them, ITF1697 (Gly-(Nalpha-Et)Lys-Pro-Arg) was stable in vivo and particularly efficacious in experimental models of disseminated endotoxemia and of cardiovascular disorders. Using intravital fluorescence microscopy, we studied the peptide cellular and molecular basis of protection in the Syrian hamster cheek pouch microcirculation subjected to ischemia/reperfusion (I/R) and in pressure elevation-induced proinflammatory responses in isolated Sprague-Dawley rat lungs. Continuous intravenous infusion of ITF1697 at 0.1 to 100 mug/kg/min nearly completely protected the cheek pouch microcirculation from I/R injury as measured by decreased vascular permeability and increased capillary perfusion. Adhesion of leukocytes and platelets to blood vessels was strongly inhibited by the peptide. ITF1697 exerted its activity at the early stages of endothelial activation and inhibited P-selectin and von Willebrand factor secretion. Further mechanistic studies in the rat lung preparation revealed that the peptide inhibited the intracellular Ca(2+)-dependent fusion of Weibel-Palade bodies with the plasma membrane. The ability of ITF1697 to inhibit the early functions of activated endothelial cells, such as the exocytosis of Weibel-Palade bodies, represents a novel and promising pharmacological tool in model of pathologies of a variety of microvascular disorders.
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PMID:ITF1697, a stable Lys-Pro-containing peptide, inhibits weibel-palade body exocytosis induced by ischemia/reperfusion and pressure elevation. 1794 65


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