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

Purine nucleotides, nucleosides, nucleobases, dinucleotides and nucleosides derivatives from acid-extracted rat liver and diaphragm were separated and quantitated by reversed-phase ion-pair high-performance liquid chromatography with a mobile phase composed of 90 mM potassium phosphate, 15 mM tetrabutylammonium hydroxide and a 1-30% methanol gradient. During 5 min of ischemia, adenine and guanine nucleotides decreased along with significant declines in NAD and increases in adenosine, inosine, hypoxanthine, xanthine, NADP and adenylosuccinate. Nitrobenzylthioinosine by gavage (5 mg/kg per day for five days) increased adenosine levels but without any alteration in nucleobase levels. Adenosine was shuttled to every available intracellular reservoir which included in declining order of magnitude GDP greater than adenosylhomocysteine greater than adenosine greater than ADP greater than AMP greater than IMP = XMP = GMP.
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PMID:Demonstration of the adenosine reservoirs with nitrobenzylthioinosine in liver and diaphragm by high-performance liquid chromatography. 339 39

This paper is a synopsis on recent reports dealing with the pharmacological basis of molsidomine-induced circulatory effects. The therapy of coronary insufficiency by molsidomine is based on different pathophysiological and pharmacological mechanisms. The inactive compound molsidomine is metabolized--mainly in the liver--to form the vasoactive and antiaggregatory compound SIN-1 and SIN-1A. Due to the gradual conversion into the active compound, the peak effects are observed only after 15 min (intravenously) or 30 to 60 min (orally). The effects are long-lasting and can be observed up to four to six hours. The c-GMP mediated dilation of various vascular sites comprise mainly the venous system (both small and large veins), resulting in a significant preload reduction, a decrease in cardiac output, a decrease in heart size and circumferential wall stress, a decrease in myocardial oxygen consumption and a therapeutically important improvement of O2-delivery versus myocardial O2-consumption. This effect results in a significant improvement of myocardial ischemia (reducing frequency of anginal attacks, improvement of exercise tolerance and of exercise induced ST-depressions). In animal experiments molsidomine diminishes infarct size and suppresses reperfusion-induced ventricular fibrillation following ischemia. Molsidomine dilates, like nitroglycerin, the large coronary arteries. Therefore, in coronary heart disease, it may improve collateral flow in addition to beneficial effects on subendocardial perfusion resulting from the reduction of ventricular wall stress. In addition to direct dilating effects on collateral vessels an improvement in perfusion of asynergistically contracting ventricular sections has been observed. In contrast to nitroglycerin, effects on peripheral resistance appear only under extremely high dosages and reflex increases in heart rate are rarely observed. In general molsidomine-induced changes (increases) in heart rate, in stroke volume (decreases), and in cardiac output (decreases) are of small magnitude. Recently interesting findings on molsidomine-induced suppression of thrombocyte aggregation, of thromboxan-synthesis inhibition and of increased prostacyclin formation have been presented, which may be important in the improvement of myocardial (micro-) circulation under ischemic conditions.
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PMID:[Pharmacological basis of therapy with molsidomine]. 689 44

The characteristics of adenosine and inosine outflow evoked by 5 min of ischemia-like conditions in vitro (superfusion with glucose-free Krebs solution gassed with 95% N2/5% CO2) were investigated on rat hippocampal slices. The viability of the slices after "ischemia" was evaluated by extracellular recording of the evoked synaptic responses in the CA1 region. The evoked dendritic field potentials were abolished after 5 min of superfusion under "ischemia" but a complete recovery occurred after 5 min of reperfusion with normal oxygenated Krebs solution. No recovery took place after 10 min of "ischemia." The addition of the adenosine A1 receptor antagonist 8-phenyltheophylline to the superfusate antagonized the depression of the evoked field potentials caused by 5 min of "ischemia." Five minutes of "ischemia" brought about a six- and fivefold increase in adenosine and inosine outflow, respectively, within 10 min. Tetrodotoxin reduced the outflow of adenosine and inosine by 42 and 33%, respectively, whereas the removal of Ca2+ caused a further increase. The NMDA receptor antagonist D(-)-2-amino-7-phosphonoheptanoic acid and the non-NMDA antagonist 6,7-dinitroquinoxaline-2,3-dione brought about small, not statistically significant decreases of adenosine and inosine outflow. The glutamate uptake inhibitor dihydrokainate did not affect the outflow of adenosine and inosine. Inhibition of ecto-5'-nucleotidase by alpha,beta-methylene ADP and GMP did not affect basal adenosine outflow but potentiated "ischemia"-evoked adenosine outflow. It is concluded that ischemia-like conditions in vitro evoke a Ca(2+)-independent adenosine and inosine outflow, through a mechanism that partly depends on propagated nervous activity but does not involve excitatory amino acids.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Investigations into the adenosine outflow from hippocampal slices evoked by ischemia-like conditions. 851 75

The aim of this study was to investigate if levels of circulating cyclic guanosine monophosphate (c-GMP) alter in preconditioning. Twenty-eight rabbits were divided into four groups. In vivo hearts were preconditioned, either with 5 min (group A, n = 8) or with 1 min (group B, n = 8) ischemia, followed by 10 min reperfusion, while groups C (n = 7) and D (n = 5) had no interventions. Protection was determined by subjecting groups A, B and C (but not D) to 30 min regional ischemia which was followed (including group D) by 2 h reperfusion. Seven blood samples were collected for the assessment of circulating c-GMP at different points of time. All results were expressed in pmol/ml using radio-immunoassay and the infarcted to risk area in percent using fluorescent particles and tetrazolium chloride (TTC). Circulating c-GMP increased during long ischemia only in group A (baseline value 47 +/- 4, long ischemic values 60.5 +/- 4 and 60.4 +/- 4, p < 0.05). Circulating c-GMP in group A was significantly higher in the middle of the long ischemia in comparison to the groups B, C and D (60.5 +/- 4 vs 43.9 +/- 4, 45.8 +/- 5 and 43.6 +/- 4, p < 0.05). Infarcted to risk ratio was lower in group A than in groups B and C (12.2 +/- 4 vs 29.6 +/- 6 and 34.2 +/- 6 respectively, p < 0.05). Circulating c-GMP is increased in classically preconditioned in comparison to ineffectively preconditioned hearts or to control groups. This elevation may be related to the protective effect of this phenomenon.
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PMID:Alterations in circulating cyclic guanosine monophosphate (c-GMP) during short and long ischemia in preconditioning. 883 42

Cavinton was introduced into the clinical practice some twenty years ago in Hungary for the treatment of cerebrovascular disorders and related symptoms. Since then, its active ingredient, vinpocetine, beside its therapeutical utilization, has become a reference compound in the pharmacological research of cognitive deficits caused by hypoxia and ischaemia as well as in the cellular and biochemical investigations related to cyclic nucleotides. In this review a survey is given on the experimental data obtained with vinpocetine and an attempt is made to outline the drug's mechanism of action. Early experiments with vinpocetine indicated five main pharmacological and biochemical actions: (1) selective enhancement of the brain circulation and oxygen utilization without significant alteration in parameters of systemic circulation, (2) increased tolerance of the brain toward hypoxia and ischemia, (3) anticonvulsant activity, (4) inhibitory effect on phosphodiesterase (PDE) enzyme and (5) improvement of rheological properties of the blood and inhibition of aggregation of thrombocytes. Later studies in various laboratories confirmed the above effects and clearly demonstrated that vinpocetine offers significant and direct neuroprotection both under in vitro and in vivo conditions. Evidence has been obtained that neuroprotective action vinpocetine is related to the inhibition of operation of voltage dependent neuronal Na(+)-channels, indirect inhibition of some molecular cascades initiated by the rise of intracellular Ca(2+)-levels and, to a lesser extent, inhibition of adenosine reuptake. Vinpocetine has been shown to be selective inhibitor of Ca(2+)-calmodulin dependent cGMP-PDE. It is assumed that this inhibition enhances intracellular a GMP levels in the vascular smooth muscle leading to reduced resistance of cerebral vessels and increase of cerebral flow. This effect might also beneficially contribute to the neuroprotective action.
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PMID:[Mechanism of action of vinpocetine]. 908 41

Nitric oxide (NO), identified as the mediator of endothelium-dependent relaxation of vascular smooth muscle, is known to cause a number of inflammatory conditions, especially in ischemia/reperfusion injury. This experimental study, using a rabbit epigastric island flap, was designed to investigate whether skin flap ischemia followed by reperfusion-influenced serum NO and c-GMP concentrations in the flap. In addition, we also investigated the premedicated effects of the NO synthase inhibitor and heparin on serum NO and c-GMP concentrations in skin flap ischemia/reperfusion. Serum NO concentration after 15, 30, 45, and 60 minutes of ischemia followed by reperfusion significantly increased compared with that in nonischemic control and elevated flaps. On the contrary, serum NO concentration was suppressed in L-NAME or aminoguanidine pretreated animals with ischemic group. Administration of heparin increased the serum NO concentration in elevated flaps, but suppressed it in ischemic flaps followed by reperfusion. The changes in serum c-GMP and NO concentrations were related in all of the experimental groups. These results suggest that NO may be derived from vascular endothelial cells and dilate peripheral vessels in compensation for ischemia.
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PMID:Physiological roles of endothelium-derived nitric oxide in the epigastric island flaps of rabbits. 941 20

Brain ischemia stimulates release from astrocytes of adenine-based purines, particularly adenosine, which is neuroprotective. Guanosine, which has trophic properties that may aid recovery following neurological damage, is present in high local concentrations for several days after focal cerebral ischemia. We investigated whether guanine-based purines, like their adenine-based counterparts, were released from astrocytes and whether their release increased following hypoxia/hypoglycemia. HPLC analysis of culture medium of rat astrocytes showed spontaneous release of endogenous guanine-based purines at a higher rate than their adenine-based counterparts. The concentration of guanosine (approximately 120 nM) and adenosine (approximately 43 nM) in the culture medium remained constant, whereas concentrations of adenine and guanine nucleotides, particularly GMP, and their metabolites increased with time. Exposure of the cultures to hypoxia/hypoglycemia for 30 min increased the extracellular concentration of adenine-based purines by 2.5-fold and of guanine-based purines by 3.5-fold. Following hypoxia/hypoglycemia extracellular adenine nucleotide levels increased further. Adenosine concentration increased, but not proportionally to nucleotide levels. Accumulation of adenosine metabolites indicated it was rapidly metabolized. Conversely, the concentrations of extracellular guanine-based nucleotides remained elevated and the concentration of guanosine continued to increase. These data indicate that astrocytes are a major source of guanine-based purines, the release of which is markedly increased following hypoxia/hypoglycemia, permitting them to exert neurotrophic effects.
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PMID:Rat cultured astrocytes release guanine-based purines in basal conditions and after hypoxia/hypoglycemia. 988 1

Adenosine increases blood flow and decreases excitatory nerve firing. In the heart, it reduces rate and force of contraction and preconditions the heart against injury by prolonged ischemia. Based on indirect kinetic arguments, an AMP-selective cytosolic 5'-nucleotidase designated cN-I has been implicated in adenosine formation during ATP breakdown. The molecular identity of cN-I is unknown, although an IMP/GMP-selective cytosolic 5'-nucleotidase (cN-II) and an ecto-5'-nucleotidase (e-N) have been cloned. We utilized the high abundance of cN-I in pigeon heart to purify a 40-kDa subunit for partial protein sequencing and subsequent cDNA cloning. We obtained a full-length clone encoding a novel 40-kDa peptide, unrelated to cN-II or e-N, that was most abundant in heart, brain, and breast muscle. Immunolocalization in heart showed a striated cytoplasmic location, suggesting association with contractile elements. Transient expression in COS-7 cells, generated a 5'-nucleotidase that catalyzed adenosine formation from AMP, which was increased during ATP catabolism. In conclusion, the cloning and expression of cN-I provides definitive evidence of its ability to produce adenosine during ATP breakdown.
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PMID:The mechanism of adenosine formation in cells. Cloning of cytosolic 5'-nucleotidase-I. 1036 22

Myocardial and endothelial damage is still a widely debated problem during the ischemia-reperfusion sequence in heart surgery. We evaluated myocardial purine metabolites, antioxidant defense mechanisms, oxidative status and endothelial dysfunction markers in 14 patients undergoing coronary artery by-pass graft (CABG). Heart biopsies were taken before aortic cross-clamping (t1), before clamp removal (t2) and 30 min after reperfusion (t3); perchloric extracts of the tissue were analyzed for glutathione, NAD, nucleotide nucleoside and base content by capillary electrophoresis (CE). In plasma samples from the coronary sinus we evaluated: nitrate and nitrite concentrations by CE, plasma glutathione peroxidase (plGPx) by ELISA, endothelin-1 (ET-1) by RIA and reactive oxygen metabolites (ROM) by colorimetric assay. During the ischemic period (t2) we observed a reduction in cellular NAD and GSH levels, as well as nitrate, nitrite and plGPx. ATP and GTP levels decreased and their catabolic products AMP, GMP, IMP, adenosine, inosine and hypoxanthine accumulated. The energy charge, ATP/ADP ratio, and nucleotide/(nucleoside + base) ratios decreased. At t3, levels of plasma ET-1 increased and monophosphate nucleotides tended to return to basal values. The energy charge did not increase but the nucleotide/(nucleoside + nucleobase) ratio recovered to some extent. Levels of nitrates plus nitrites continued to decrease. No significant variation in ROM levels was observed. Our data indicate that oxidative stress and endothelial damage are major events during CABG, overwhelming the scavenging capacity of the myocyte and preventing restoration of the normal energy balance for 30 min after reperfusion. The AMP deaminase pathway leading to IMP production is active during ischemia and adenosine is not the main compound derived from ATP break-down in the human heart. The possible role of extracorporeal circulation is also discussed.
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PMID:Cardiac surgery: myocardial energy balance, antioxidant status and endothelial function after ischemia-reperfusion. 1250 69

Experimental evidence has been presented connecting melatonin with the prevention or treatment of gastrointestinal disorders either by the scavenging properties of active oxygen or by receptor-mediated stimulation of gene expression of neutralizing enzymes. Prostaglandins and nitric oxide are important neuroimmunomodulators in digestive physiology and different studies have indicated that the protective properties of melatonin may be explained by prostaglandin and/or nitric oxide mechanisms. The aim of the present study was to examine the effect of intraperitoneal administration of melatonin on in vivo changes in PGE(2), generated in gastric mucosal lesions by ischemia-reperfusion. Cyclic GMP nucleotide was also studied as an index of the principal enzymatic activity involved in the metabolism of nitric oxide, the nitric oxide synthase. The different immunological tests showed that the intraperitoneal administration of melatonin prevents the postischemic decrease in prostaglandins. The concentration of this eicosanoid in the rat mucosa treated with 20 mg.kg(-1) of melatonin was significantly higher (p < 0.05) than that in the control rats. The amount of cyclic GMP in the stomach decreased because of ischemia-reperfusion. In treated animals however, a marked increase occurred in concentrations of GMP, but the difference was not statistically significant. The results suggest that the mechanism of protection afforded by melatonin against lesions induced by gastric ischemia-reperfusion may be due to stimulation of the synthesis of eicosanoid protectors during the ischemic process.
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PMID:Melatonin modulates the effects of gastric injury in rats: role of prostaglandins and nitric oxide. 1287 1


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