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)

Reperfusion damage is largely due to the adherence of polymorphonuclear leukocytes to the endothelium initiated by adhesion molecule upregulation. The reduced endothelial nitric oxide release during ischemia may be involved in the upregulation of intercellular adhesion molecule 1. In this study, we tested if nitric oxide donors suppress polymorphonuclear leukocyte adherence to activated endothelial cells by inhibition of the intercellular adhesion molecule 1 surface expression. Confluent human umbilical vein endothelial cells were stimulated with tumor necrosis factor alpha (300 U/mL) after preincubation with increasing concentrations of the nitric oxide donors CAS 1609 (0.005-5 mM/L) and 3-(4-morpholinyl)-sydnonimine (0.01-1 mM/L). Intercellular adhesion molecule 1 surface expression was measured in a cell surface enzyme-linked immunosorbent assay, intercellular adhesion molecule 1 mRNA by Northern analysis. Human saphenous vein endothelial cells were transfected with the inducible nitric oxide synthase gene and stimulated with tumor necrosis factor alpha (300 U/mL). Fluorescein green-labeled polymorphonuclear leukocytes adhering to activated human umbilical vein endothelial cells/human saphenous vein endothelial cells were quantified by epifluorescent microscopy. The intercellular adhesion molecule 1 surface expression of activated human umbilical vein endothelial cells/human saphenous vein endothelial cells was significantly diminished to 40 to 60% of the maximum after treatment with CAS 1609, 3-(4-morpholinyl)-sydnonimine, or transfection with the inducible nitric oxide synthase gene. Intercellular adhesion molecule 1 mRNA was diminished by CAS 1609 and 3-(4-morpholinyl)-sydnonimine in the same manner. The functional relevance of our data was shown by reduction of polymorphonuclear leukocyte adherence to activated human umbilical vein endothelial cells/human saphenous vein endothelial cells following treatment with CAS 1609 and 3-(4-morpholinyl)-sydnonimine or transfection with inducible nitric oxide synthase. Tumor necrosis factor-induced polymorphonuclear leukocyte adherence was abolished by blocking antibody against intercellular adhesion molecule 1. Thus, exogenous or endogenous substitution of nitric oxide diminishes the expression of endothelial intercellular adhesion molecule 1 and its mRNA following tumor necrosis factor alpha stimulation. This results in a reduced polymorphonuclear leukocyte adherence to activated endothelium.
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PMID:NO reduces PMN adhesion to human vascular endothelial cells due to downregulation of ICAM-1 mRNA and surface expression. 1068 Jun 42

HNS-32 (N1,N1-dimethyl-N2-(2-pyridylmethyl)-5-isopropyl-3, 8-dimethylazulene-1-carboxamidine: CAS 186086-10-2) is a newly synthesized compound, and possesses antiarrhythmic properties with vasodilator action in dog hearts. The aim of this study was to investigate the dose-dependent effects of HNS-32 on ischemia- and/or reperfusion-induced ventricular arrhythmias in anesthetized rats in vivo and compared with those of mexiletine. Saline or drugs were administered intravenously 5 min prior to coronary artery occlusion. On the ischemia-induced ventricular arrhythmias, HNS-32 showed dose-dependent reduction of total number of premature ventricular complexes (PVC) from 2091+/-225 to 656+/-116 and 286+/-69 beats/30 min (p < 0.05), the ventricular tachycardia (VT) duration from 183+/-33 to 28+/-9 and 4+/-2 sec (p < 0.05), the incidence of VT from 100 to 90 (n.s.) and 40% (p < 0.05), and the incidence of ventricular fibrillation (VF) from 50 to 0 and 0% (p < 0.05) with 3 and 5 mg/kg, respectively. Mexiletine also reduced these parameters to 936+/-159 beats/30 min (p < 0.05), 39+/-22 sec (p < 0.05), 90% (n.s.) and 10% (n.s.), respectively. HNS-32 completely suppressed the late reperfusion-induced arrhythmias, however mexiletine did not affect them. On the early reperfusion-induced ventricular arrhythmias, HNS-32 showed dose-dependent reduction of VT duration from 126+/-34 to 37+/-12 and 3+/-2 sec (p < 0.05), incidence of VT from 100 to 90 (n.s.) and 40% (p < 0.05), incidence of VF from 100 to 10 and 0% (p < 0.05), and mortality rate from 90 to 0 and 0% (p < 0.05), with 3 and 5 mg/kg, respectively. Mexiletine also reduced these parameters to 16+/-9 sec (p < 0.05), 80 (n.s.), 50 (p < 0.05), and 10% (p < 0.05), respectively. HNS-32 significantly reduced the heart rate in a dose-dependent manner, from 399+/-14 to 350+/-8 and 299+/-10 beats/min (p < 0.05) with 3 and 5 mg/kg, respectively. The antiarrhythmic effects of HNS-32 were more potent than that of the similar dose of mexiletine against occlusion-induced and reperfusion-induced arrhythmias in in vivo rats.
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PMID:Effects of HNS-32, a novel antiarrhythmic drug, on ventricular arrhythmias induced by coronary artery occlusion and reperfusion in anesthetized rats. 1082 31

7-Hydroxycoumarin (CAS 93-35-6, 7-HC) is the main coumarin (1,2-benzopyrone) metabolite and the therapeutic active molecule. It exhibits antioxidant properties in vitro and may share with other coumarin derivatives vasodilator effects. The aim of the study was to assess the effects of 7-HC on isolated perfused and ischemic-reperfused rat heart. After a 10-min perfusion, an increase in the coronary flow was observed with 7-HC at 10(-4) mol/l (p = 0.002) as well as an increase in left ventricular developed pressure with 7-HC at 10(-5) mol/l (p = 0.038). The increase in coronary flow is not solely explained by the increase in inotropism. It appears to be also induced through a direct vasodilator effect which, however, does not involve the release of vasodilator prostaglandins since it was not inhibited by indometacin. After the 30-min global ischemia and the 45-min reperfusion period, 7-HC at 10(-5) mol/l induced an increase in left ventricular developed pressure (p = 0.042) and in the ratio of heart rate x left ventricular developed pressure over oxygen consumption (p = 0.036).
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PMID:Effects of 7-hydroxycoumarin (umbelliferone) on isolated perfused and ischemic-reperfused rat heart 1110 30

The aim of this study was to investigate the protective effect of gastric mucus against Helicobacter pylori-induced gastric mucosal injury, measuring intramucosal mucus and the surface hydrophobicity. Male Sprague-Dawley rats' stomachs were exposed to H. pylori suspension (1 x 10(5) ml) plus 1 ml of urea solution (400 mg/dl) with gastric ischemia (withdrawal of 3 ml of blood) for 60 min, 60 min after pretreatment with teprenone (CAS 6809-52-5) (50 mg/rat, intragastric). The control rats were treated in the same manner without pretreatment with teprenone. A high concentration of intragastric ammonia was generated 60 min after administration of H. pylori plus urea in both the control and the teprenone-pretreated rats. A reduction in transmucosal potential difference, formation of hemorrhagic gastric lesions, and impairment in both intramucosal mucus and surface hydrophobicity were observed in the corpus of the control rats. However, the pretreatment with teprenone prevented such a reduction in potential difference and the development of gastric lesions against ammonia through the preservation of gastric mucus. The preservation of gastric mucus might protect gastric mucosa against attacks by H. pylori, suggesting that the mechanism of H. pylori-associated gastric injury is associated with the decrease in gastric mucus.
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PMID:Effect of teprenone on gastric mucosal injury induced by Helicobacter pylori in rats. 1119 Jul 77

A new medium (pH 5.6 reached by addition of 0.1 mol/l acetate buffer, 37 degrees C, 60 min) was established for detecting anti-free radical compounds in the 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay. DPPH bleaching activities of typical antioxidants appeared generally weaker at pH 8.0 (the measured ethanol solution pH by the classical DPPH assay method) than at pH 5.6. Nilvadipine (CAS 75530-68-6), a lipophilic calcium antagonist, enhanced the bleaching much more at pH 5.6 than at pH 8.0. Nifedipine (CAS 21829-25-4) and amiodipine (amiodipine besilate, CAS 88150-42-9) showed some effect, but the other five calcium antagonists failed to bleach DPPH at any pH tested (pH 4.4-8.0). Probucol and beta-carotene (standard antioxidant) showed nearly the same bleaching activity as nilvadipine. Captopril, glutathione and bilirubin were weaker anti-free radical compounds at pH 5.6. No intermediating participation of superoxide radicals and hydroxyl radicals were observed in the DPPH assay, both at pH 8.0 and 5.6. Thus, nilvadipine was shown to be an efficient free-radical scavenger only at around pH 5.6, a weak acidic condition which may occur as a result of inflammation and/or ischemia-reperfusion.
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PMID:Effect of nilvadipine in weak acidic medium by 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay. 1130 37

The antioxidant effect of the non-specific nitric oxide synthase inhibitor, N omega-nitro-L-arginine methyl ester (CAS 50903-99-6, L-NAME), was studied in a rat model of global cerebral ischemia. In addition, the influence of low doses of L-NAME on nitric oxide production, measured as nitrate/nitrite end products, was investigated in the ischemic rats. Ischemia was induced by bilateral clamping of the common carotid arteries for 60 min followed by a reperfusion period for 60 min. L-NAME was administered intraperitoneally in the doses of 1 and 3 mg kg-1, twice, immediately after ischemia and 15 min before termination of the experiment. The drug decreased the elevated activity of lactate dehydrogenase (LDH, 1.1.1.27) as well as the increased level of lipid peroxide in the rat brain. L-NAME was also capable to normalize the reduced activity of superoxide dismutase (SOD, 1.15.1.1) that was observed after ischemia. Improvement of these parameters in L-NAME-treated rats was parallel to normalization of nitric oxide production in the treated animals. These results indicate that inhibition of nitric oxide synthase, induced by L-NAME, could improve the oxidative status of the rat brain after ischemia.
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PMID:Antioxidant effect of N omega-nitro-L-arginine methyl ester (L-NAME) on global cerebral ischemia in a rat model. 1155 22

HNS-32 [N(1),N(1)-dimethyl-N(2)-(2-pyridylmethyl)-5-isopropyl-3,8-dimethylazulene-1- carboxamidine] (CAS Registry Number: 186086-10-2) is a newly synthesized azulene derivative. Computer simulation showed that its three dimensional structure is similar to that of the class Ib antiarrhythmic drugs, e.g., lidocaine or mexiletine. HNS-32 potently suppressed ventricular arrhythmias induced by ischemia due to coronary ligation and/or ischemia-reperfusion in dogs and rats. In the isolated dog and guinea pig cardiac tissues, HNS-32 had negative inotropic and chronotropic actions, prolonged atrial-His and His-ventricular conduction time and increased coronary blood flow. In the isolated guinea pig ventricular papillary muscle, HNS-32 decreased maximal rate of action potential upstroke (Vmax) and shortened action potential duration (APD). These findings suggest that HNS-32 inhibits inward Na+ and Ca2+ channel currents. In the isolated pig coronary and rabbit conduit arteries, HNS-32 inhibited both Ca2+ channel-dependent and -independent contractions induced by a wide variety of chemical stimuli. HNS-32 is a potent inhibitor of protein kinase C (PKC)-mediated constriction of cerebral arteries. It is likely to block both, Na+ and Ca2+ channels expressed in cardiac and vascular smooth muscles. These multiple ion channel blocking effects are largely responsible for the antiarrhythmic and vasorelaxant actions of HNS-32. This drug may represent a novel approach to the treatment of arrhythmias.
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PMID:A review of HNS-32: a novel azulene-1-carboxamidine derivative with multiple cardiovascular protective actions. 1183 Jul 49

Loss of inhibitory GABAergic modulation may induce hyperexcitability of neuronal elements and potentiate their vulnerability to excitotoxic injury. It has been also found that the adenosine system interacts with the GABAergic system during ischemia and anoxia where the adenosine receptors as well as the GABAergic receptors may conscript the same intracellular pathway to increase tolerance to ischemia. Therefore, it was aimed to study whether dipyridamole (CAS 58-32-2), an adenosine uptake inhibitor, or adenosine (CAS 58-61-7) could affect the rat brain gamma-aminobutyric acid (GABA, CAS 56-12-2) level after induction of cerebral ischemia, and to test their effect on the lactate dehydrogenase (LDH) activity of the ischemic rat brain. Ischemia was induced by bilateral clamping of the common carotid arteries for 60 min followed by reperfusion for other 60 min. Dipyridamole was administered alone and in combination with adenosine and the effect of the drugs on the brain GABA level as well as on LDH activity was determined. The results show that dipyridamole could protect the brain of rats against the ischemic insult, while adenosine when administered separately failed to influence the selected parameters. Protection of the rat brain by dipyridamole might be related to the elevated level of GABA.
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PMID:Influence of inhibition of adenosine uptake on the gamma-aminobutyric acid level of the ischemic rat brain. 1208 19

The effects of ozagrel (CAS 82571-53-7), a thromboxane A2-synthetase inhibitor, and norphenazone (CAS 89-25-8), a free-radical scavenger, on cerebral infarction were assessed using the suture-induced middle cerebral artery occlusion (MCAO) model and a microthrombosis model. In the former model, the middle cerebral artery was occluded for 2 h, and the infarction area and volume were evaluated 24 h after the start of reperfusion. In the latter model, microthrombosis were induced by two injections of sodium laurate (interval, 2 days) into the internal carotid artery, and the neurologic deficits were evaluated on the day afer the 2nd injection. Ozagrel at 3 mg/kg decreased both the area and volume of the cortical infarction after ischemia-reperfusion of the middle cerebral artery. Ozagrel also had suppressive effects on the neurologic deficits in the microthrombosis model. Norphenazone at 1 and 3 mg/kg had no clear effects in either model. Since the suture-induced MCAO model and the microthrombosis model are models for occlusion-reperfusion of the major cerebral arteries and lacunar infarction, respectively, these results suggest a highly beneficial effect of ozagrel in the clinical therapy for stroke.
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PMID:Effect of ozagrel, a selective thromboxane A2-synthetase inhibitor, on cerebral infarction in rats. Comparative study with norphenazone, a free-radical scavenger. 1465 Mar 60

DY-9760e (3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate, CAS 162496-41-5) is a novel calmodulin antagonist that is being evaluated for the treatment of ischemia. The objective of this study was to characterize the pharmacokinetics and disposition of DY-9760e in rats and monkeys. After a 6 h continuous infusion at 1 mg/kg/h to male rats, the plasma concentration of unchanged DY-9760, as the anhydrous free base of DY-9760e, declined with a terminal half-life of 3.0 h. In monkeys, the plasma concentration of DY-9760 following a 4 h continuous infusion at 1 mg/kg/h declined with a terminal half-life of 3.8 h. Total clearance was 18.3 ml/min/kg in rats and 16.7 ml/min/kg in monkeys. The pharmacokinetics of DY-9760e was linear within a dose range from 1 mg/kg to 16 mg/kg in monkeys. After intravenous bolus administration of 14C-DY-9760e to rats, the radioactivity was widely distributed throughout the body except for the brain and testis. In the brain, which is the target organ of this compound, the concentrations of unchanged DY-9760 in rats were much lower than the corresponding plasma concentrations. These results indicated that the permeability of DY-9760 into the brain was restricted. In contrast, the brain concentrations of the N-dealkylated metabolite DY-9836 were approximately 2- to 3-fold higher than those observed in the plasma. The administered radioactivity was excreted mostly in the feces (95.2% in rats, 83.6% in monkeys), and the biliary excretion of the radioactivity in bile duct-cannulated rats was 86.2% within 48 h, part of which (11.1%) was re-absorbed. The urinary excretion of unchanged DY-9760 was less than 0.5% in both species. The metabolic profile characterized by thin-layer chromatography demonstrated that most of the radioactivity in the urine and bile referred to many polar metabolites. These results indicate that DY-9760e is eliminated mainly through hepatic metabolic clearance in both rats and monkeys.
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PMID:Pharmacokinetics and disposition of DY-9760e, a novel calmodulin antagonist, in rats and monkeys. 1581 85


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