Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

In the brain stem glycine is associated with multiple sensory and visceral regulations, being involved in, for instance, cardiovascular, respiratory and auditory functions. We here studied the mechanisms of the release of preloaded [(3)H]glycine from mouse brain stem slices in a superfusion system. A depolarizing concentration of K(+) ions (50 mM) evoked glycine release, but in the absence of Ca(2+) the effect was attenuated, indicating that a part of the evoked release represents Ca(2+)-dependent exocytosis. The Ca(2+)-independent release was enhanced by omission of Na(+) and Cl(-). The stimulatory effect of extracellular glycine confirmed the involvement of transporters functioning in a reverse direction. A part of the release is mediated by Na(+) and Cl(-) channels, since it was inhibited by the inhibitors of these, riluzole and 4-acetamido-4'-isothiocyanostilbene-2,2'-disulphonate, respectively. Glycine release was potentiated by the activation of protein kinase C and diminished by increasing cyclic guanosine monophosphate levels with a phosphodiesterase inhibitor, zaprinast. The release was also modulated by the phospholipase inhibitor quinacrine and the tyrosine kinase inhibitor genistein. Adenosine A(1) receptors likewise regulate glycine release, since it was enhanced by their agonist R(-)N(6)-(2-phenylisopropyl)adenosine, which effect was blocked by the antagonist 8-cyclopentyl-1,3-dipropylxanthine. The ionotropic glutamate receptor agonists N-methyl-D: -aspartate, kainate and 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate failed to have any effects contrary to their effects in higher brain regions, e.g., in the hippocampus. The group I and III metabotropic glutamate receptor agonists (S)-3,5-dihydroxyphenylglycine and O-phospho-L: -serine, respectively, increased the release in a receptor-mediated manner. Glycine release in the brain stem was also markedly enhanced by cell-damaging conditions, including hypoxia, hypoglycemia and ischemia.
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PMID:Mechanisms of glycine release in mouse brain stem slices. 1860 Apr 48

Cerebral ischemia resulting from transient or permanent cerebral artery occlusion leads to neuronal cell death, and eventually causes neurological impairments. Tadalafil (Cialis)is a long-acting phosphodiesterase type-5 (PDE-5) inhibitor used to treat erectile dysfunction. The therapeutic effects of PDE-5 inhibitors on chronic obstructive pulmonary disease, prostate hyperplasia, hypertension, and coronary heart disease have been reported. The present study investigated the effects of tadalafil on short-term memory, cyclic guanosine monophosphate (cGMP) level, apoptotic neuronal cell death, and cell proliferation in the hippocampus following transient global ischemia in gerbils. For this study, a step-down avoidance task, cGMP assay, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, and immunohistochemistry for caspase-3 and 5-bromo-2'-deoxyuridine were performed. The results revealed that ischemic injury increased apoptotic neuronal cell death in the hippocampal CA1 region, impaired short-term memory, and decreased cGMP level. Ischemic injury enhanced cell proliferation in the hippocampal dentate gyrus. Tadalafil treatment improved short-term memory by suppressing ischemia-induced apoptotic neuronal cell death in the hippocampal CA1 region, and decreased cGMP level. Also, tadalafil suppressed the ischemia-induced increase in cell proliferation in the hippocampal dentate gyrus. We showed that tadalafil can overcome ischemia-induced apoptotic neuronal cell death, thus facilitates recovery following ischemic cerebral injury.
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PMID:Tadalafil improves short-term memory by suppressing ischemia-induced apoptosis of hippocampal neuronal cells in gerbils. 1901 Mar 46

Resveratrol pretreatment can protect the heart by inducing pharmacological preconditioning. Whether resveratrol protects the heart when applied at reperfusion remains unknown. We examined the effect of resveratrol on myocardial infarct size when given at reperfusion and investigated the mechanism underlying the effect. Isolated rat hearts were subjected to 30 min ischemia followed by 2 h of reperfusion, and myocardial samples were collected from the risk zone for Western blot analysis. Mitochondrial swelling was spectrophotometrically measured as a decrease in absorbance at 520 nm (A(520)). Resveratrol reduced infarct size and prevented cardiac mitochondrial swelling. Resveratrol enhanced GSK-3beta phosphorylation upon reperfusion, an effect that was mediated by the cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG) pathway. Resveratrol translocated GSK-3beta from cytosol to mitochondria via the cGMP/PKG pathway. Further studies showed that mitochondrial GSK-3beta was co-immunoprecipitated with cyclophilin D but not with VDAC (voltage dependent anion channel) or ANT (adenine nucleotide translocator). These data suggest that resveratrol prevents myocardial reperfusion injury presumably by targeting the mPTP through translocation of GSK-3beta from cytosol to mitochondria. Translocated GSK-3beta may ultimately interact with cyclophilin D to modulate the mPTP opening.
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PMID:Mechanism for resveratrol-induced cardioprotection against reperfusion injury involves glycogen synthase kinase 3beta and mitochondrial permeability transition pore. 1913 50

We studied the effect of adaptation to chronic immobilization stress on the contents of cyclic adenosine monophosphate and cyclic guanosine monophosphate in myocardial tissue during coronary occlusion and reperfusion. The contents of cyclic adenosine monophosphate and cyclic guanosine monophosphate in the ischemic area and nonischemic myocardium of unadapted rats increased during coronary artery ligation for 10 min. Reperfusion for 10 min was followed by an increase in the content of cyclic adenosine monophosphate. During coronary occlusion, the content of cyclic adenosine monophosphate in the myocardium of stress-adapted rats increased less significantly than in control animals. No significant differences were found in the content of cyclic guanosine monophosphate in control and adapted rats. Our results suggest that poor response of the myocardial cyclic nucleotide system to ischemia/reperfusion in adapted animals is associated with the antiarrhythmic and cardioprotective effect of adaptation.
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PMID:Effect of stress adaptation on cyclic nucleotide content in myocardial tissue during acute ischemia/reperfusion. 1914 88

The second messenger cyclic guanosine monophosphate (cGMP) plays many roles during nervous system development. Consequently, cGMP production shows complex patterns of regulation throughout early development. Elevated glutamate levels are known to increase cGMP levels in the mature nervous system. A number of clinical conditions including ischemia and perinatal asphyxia can result in elevated glutamate levels in the developing brain. To investigate the effects of elevated glutamate levels on cGMP in the developing cortex we exposed mouse brain slices to glutamate or N-methyl D-aspartate (NMDA). We find that at early postnatal stages when the endogenous production of cGMP is high, glutamate or NMDA exposure results in a significant lowering of the overall production of cGMP in the cortex, unlike the situation in the mature brain. However, this response pattern is complex with regional and cell-type specific exceptions to the overall lowered cGMP production. These data emphasize that the response of the developing brain to physiological disturbances can be different from that of the mature brain, and must be considered in the context of the developmental events occurring at the time of disturbance.
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PMID:Elevated glutamate and NMDA disrupt production of the second messenger cyclic GMP in the early postnatal mouse cortex. 1917 58

Adrenomedullin (ADM) is a novel potent vasodilatory peptide that was isolated from human pheochromocytoma cells in 1993. It consists of 52 amino acids with 1 intramolecular disulfide bond and a C-terminal amide structure. The vasodilatory effect of ADM is mediated by the activation of secondary messengers, including cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) that are induced by nitric oxide (NO). The objective of the present study was to ascertain the protective effect of ADM against ischemia/reperfusion (I/R) injury on isolated perfused rat liver (IPRL) model after 60 min of warm ischemic preservation and identify the pathways involved. Administration of ADM in the perfusate during initial perfusion and in the preserving fluid during reperfusion after preservation augmented portal flow by 1.3-fold (p < 0.01), increased bile production by 2.3-fold (p < 0.01), reduced the release of lactate dehydrogenase (LDH) to 0.73-fold (p < 0.05), increased oxygen consumption by 1.28-fold (p < 0.01), and augmented tissue cAMP by 1.8-fold (p < 0.05) those observed in the absence of ADM. However, ADM administration did not increase tissue cGMP and the uptake of hyaluronio acid, which are the functions of endothelial cells. Histological examination revealed that ADM administration resulted in an improvement in the structural changes induced by the I/R insult; however, it could not prevent the destruction of the sinusoidal endothelial cells. These results indicated that the ADM-mediated increased portal flow in the liver under an I/R insult is not induced by the NO-cGMP pathway but by the activation of cAMP.
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PMID:Adrenomedullin ameliorates ischemia reperfusion injury in rat livers. 1966 70

Acute kidney injury (AKI) is a syndrome characterized by an acute renal cell injury that leads to sudden loss of renal function. There are currently no clinically validated treatments for AKI besides substituting renal function by dialysis. However, new biomarkers will allow an earlier diagnosis, thus providing a window of opportunity for therapeutic intervention. Tyrphostins are a family of compounds originally designed as protein tyrosine kinase inhibitors. However, some molecules of this family have additional actions, such as inhibition of guanylate and adenylate cyclases, mitochondrial uncoupling or antioxidant effects. We review the potential role of tyrphostins in the prophylaxis and treatment of acute kidney injury on the basis of published studies on animals, in vitro experiments and piecemeal information from humans. The AG 490 and AG 126 tyrphostins have recently been shown to protect from AKI in experimental animal models of ischemia-reperfusion and sepsis-induced injury. AG 490 protects from cyclosporin-induced AKI and AG 1714 protects from cisplatin nephrotoxicity. AG 490 is nephroprotective by inhibiting oxidative stress-related Janus activated kinase-2 (JAK2) activation. Potential applications of AG490 or derivative molecules include AKI of nephrotoxic or ischemic nature, or a combination of both, as may occur in the immediate postransplant period. The molecular targets of AG 126 and AG 1714 are less well characterized. In conclusions, different tyrphostins are nephroprotective in animal models of AKI. The characterization of the molecular targets involved will allow the design of novel therapies that may reach the clinical trial stage.
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PMID:Tyrphostins as potential therapeutic agents for acute kidney injury. 2015 66

Nitric oxide (NO) and B-type natriuretic peptide (BNP) are protective against ischemia-reperfusion injury as they increase intracellular cGMP level via activation of soluble (sGC) or particulate guanylate cyclases (pGC), respectively. The aim of the present study was to examine if the cGMP-elevating mediators, NO and BNP, share a common downstream signaling pathway via cGMP-dependent protein kinase (PKG) in cardiac cytoprotection. Neonatal rat cardiac myocytes in vitro were subjected to 2.5 h simulated ischemia (SI) followed by 2 h reoxygenation. Cell viability was tested by trypan blue exclusion assay. PKG activity of cardiac myocytes was assessed by phospholamban (PLB) phosphorylation determined by western blot. Cell death was 34 +/- 2% after SI/reoxygenation injury in the control group. cGMP-inducing agents significantly decreased irreversible cell injury: the cGMP analog 8-bromo-cGMP (8-Br-cGMP, 10 nM) decreased it to 13 +/- 1% (p < 0.001), the direct NO-donor S-nitroso-N-acetylpenicillamine (SNAP, 1 microM) to 18 +/- 6% (p < 0.05) and BNP (10 nM) to 12 +/- 2% (p < 0.001), respectively. This protective effect was abolished by the selective PKG inhibitor KT-5823 (600 nM) in each case. As PLB is not a unique reporter for PKG activity since it is also phosphorylated by protein kinase A (PKA), we examined PLB phosphorylation in the presence of the PKA inhibitor KT-5720 (1 microM). The ratio of pPLB/PLB significantly increased after administration of both BNP and 8-Br-cGMP under ischemic conditions, which was abolished by the PKG inhibitor. This is the first demonstration that elevated cGMP produced either by the sGC activator SNAP or the pGC activator BNP exerts cytoprotective effects via a common downstream signaling pathway involving PKG activation.
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PMID:Role of cGMP-PKG signaling in the protection of neonatal rat cardiac myocytes subjected to simulated ischemia/reoxygenation. 2034 14

The distribution of cyclic GMP, cyclic AMP and related enzymes in the vertebrate retina, together with factors regulating their levels, are described. Photo-receptor cells in retinas from all species examined contain very high levels of cyclic GMP and high activities of both guanylate cyclase and cyclic GMP phosphodiesterase. In more proximal regions of the retina, cyclic GMP is found at concentrations similar to that of brain. Guanylate kinase and GDP kinase, enzymes involved in GMP metabolism, also have increased activities in photoreceptor cell layers although their pattern of distribution does not exactly parallel that of cyclic GMP. The concentration of cyclic AMP is fairly uniform throughout the retina and at a level similar to that found in other areas of the CNS. However adenylate cyclase has an uneven distribution with particularly high activity in the inner plexiform layer. Cyclic nucleotide levels in retina may be modified by several factors. Light decreases both cyclic nucleotides in rod-dominant retinas, although we have not observed similar changes in cone-dominant retinas. Anoxia or ischemia elevates cyclic AMP and decreases cyclic GMP, similar to other areas of CNS, while incubation of retina in Ca(++)- free media markedly increases cyclic GMP levels, an effect opposite that seen in brain tissue. Depolarization of retina with high K(+) causes a modest elevation of cyclic AMP but has no effect on cyclic GMP, which is also significantly different from the response in brain. Cyclic AMP levels in retina however, can be elevated by dopamine which is an effect similar to that in striatum. These data indicate that there are probably multiple cyclic GMP and cyclic AMP systems in retina, some of which may be unique to this tissue.
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PMID:Localization and roles of cyclic nucleotide systems in retina. 2048 44

Vascular endothelium plays a key role in the local regulation of vascular tone and vascular architecture by release of vasodilator and vasoconstrictor substances, as well as factors with pro-coagulant, anticoagulant, fibrinolytic, antibacterial properties, growth factors, chemokines, free radicals, etc. Release of endothelium-derived relaxing factors such as nitric oxide (NO), prostaglandins and endothelium-derived hyperpolarizing factor, as well as vasoconstricting factors such as endothelin, superoxide and thromboxanes play an influential role in the maintenance and regulation of vascular tone and the corresponding peripheral vascular resistance. Under physiological conditions, the release of anticoagulant and smooth muscle relaxing factors exceeds the release of other substances. The first part of this review presents the functions of the endothelium itself, the nature of the endothelium-derived relaxing factor, its production by NO synthases, mechanisms of its action via activation of soluble guanylyl cyclase and production of cyclic 3'-5'-guanosine monophosphate. The resulting biological effects include vasodilatation, regulation of vessel wall structure, increased regional blood perfusion, lowering of systemic blood pressure, antithrombosis and antiatherosclerosis effects, which counteract the vascular actions of endogenous vasoconstrictor substances. Impaired endothelial function, either as a consequence of reduced production/release or increased inactivation of endothelium-derived vasodilators, as well as interactions of NO with angiotensin, reactive oxygen species and oxidized lipoproteins, has detrimental functional consequences and is one of the most important cardiovascular risk factors. Therefore the second part of this review assesses the pathophysiologic impact of the endothelium in examples of cardiovascular pathologies, e.g. endotheliopathies caused by increased angiotensin production, lipid peroxidation, ischemia/reperfusion or diabetes.
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PMID:Nitric oxide--the endothelium-derived relaxing factor and its role in endothelial functions. 2115 95


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