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)

Nitric oxide (NO) is a mediator that modulates vessel wall tone and hemostatic-thrombotic balance. Platelet function is regulated by NO generated from platelets, endothelial cells and leukocytes. Nitric oxide has been shown to inhibit platelet adhesion, aggregation, and stimulate disaggregation of preformed platelet aggregates. Many of the effects of NO are mediated by its stimulation of guanylate cyclase and the formation of cyclic GMP and its subsequent transduction mechanism. In vivo, NO is likely to interact with prostacyclin, metabolites of ecto-nucleotidase, and lipoxygenase to modulate platelet function in a synergistic manner. An imbalance of NO production (deficiency or overproduction) has been implicated in the pathogenesis of various vascular disorders including thrombosis, atherosclerosis, septicemia, and ischemia-reperfusion injury. It is likely that some of detrimental effects of NO are mediated through its reaction with superoxide anion to form the potent oxidant, peroxynitrite. Nitric oxide gas and NO donors are used for the pharmacological treatment of various vascular disorders. Because inhaled NO has been documented to improve systemic oxygenation and reduce the need for extracorporeal membrane oxygenation, it has been widely used in neonates with severe hypoxemia. An inhibition of platelet function, resulting in a prolonged bleeding time, has been shown in adults receiving inhaled NO. Because bleeding complications may occur in high-risk infants, it is important to evaluate the effect of inhaled NO on platelet function and its correlation with clinical consequences such as intracranial hemorrhage. For these reasons, hemostasis should be carefully monitored during the administration of inhaled NO to critically ill neonates.
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PMID:Nitric oxide and platelet function: implications for neonatology. 935 13

Stimulation of NMDA receptor increases NO-dependent cGMP synthesis. A significantly higher cGMP level was observed in hippocampus (about 8-fold increase) than in cerebral cortex (2.5-fold increase), as compared to basal value. The activity of NO synthase (NOS) and the basal level of cGMP in unstimulated slices were only slightly higher in hippocampus than in the cortex. About 60% of NOS total activity was found in the brain membrane fraction. The enzyme activity was not affected by glucocorticoids, even after 20 days of hydrocortisone treatment in dose of 40 mg/kg b.w. Brain ischemia induced by ligation of the both common carotid arteries in gerbils (Meriones unquiculatus) significantly increased NOS activity as well as cGMP and putrescine concentrations but decreased mono-ADP-ribosolation of proteins. Changes of NOS activity and cGMP concentration evoked by ischemia were decreased by specific inhibitor of the neuronal form of NOS (nNOS), 7-nitrodazole and the inhibitor of guanylate cyclase, LY 83,583 administered respectively in a dose of 25 mg/kg b.w. and 6 mg/kg b.w. 5 min. before ischemia. The inhibitor of nNOS, 7NI, did not change the concentration of putrescine during ischemia and reperfusion. Our results indicated that these inhibitors could protect the brain against excessive production of nitric oxide and biochemical processes dependent on it. In this way they may offer a new strategy in the therapy of brain ischemia.
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PMID:[Influence of NMDA receptor stimulation in brain cortex and hippocampus on NO dependent cGMP synthase. Effect of ischemia on NO related biochemical processes during recirculation]. 977 Jun 92

The aim of our studies was to investigate hormonal prevention of hepatic preservation damage by the atrial natriuretic peptide (ANP) and the mechanisms involved. Isolated perfusion of rat livers was performed in a nonrecirculating fashion. Twenty minutes of preischemic perfusion was performed with or without different concentrations of ANP, followed by 24-hour storage in cold University of Wisconsin (UW) solution. Two hundred nanomoles of ANP prevented hepatocellular damage during a 2-hour reperfusion period as indicated by a marked attenuation of the sinusoidal efflux of lactate dehydrogenase (LDH) and purine nucleoside phosphorylase (PNP), and by reduced Trypan blue uptake. Furthermore, postischemic bile flow as an indicator of liver function was significantly improved by about 60% with 200 nmol/L ANP. No protection was conveyed by 20 nmol/L ANP nor by pretreatment with 200 nmol/L ANP for only 10 minutes. The effects of ANP seemed to be mediated by the guanylate cyclase-coupled A (GC-A) receptor and cyclic guanosine monophosphate (cGMP): whereas expression of both GC-A and GC-B receptors as well as of the GC-C receptor was found, cGMP did protect from ischemia-reperfusion damage, but selective ligands of the B and C receptor did not. To begin to determine the mechanisms of ANP-mediated protection, different parameters were investigated: ANP had no effect on portal pressure as an indicator of hepatic circulation, nor on intracellular energy depletion determined by adenosine nucleotide concentration. However, the marked augmentation of nuclear factor kappaB (NF-kappaB) binding activity during reperfusion was prevented in ANP-pretreated livers. In conclusion, pretreatment with ANP protects the rat liver from cold ischemia-reperfusion damage. This effect is mediated via the GC-A receptor and cGMP, and may be linked to an influence of ANP on NF-kappaB activation. Thus, ANP signaling via the GC-A receptor should be considered as a new pharmacological target to prevent preservation injury of the liver.
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PMID:The guanylate cyclase-coupled natriuretic peptide receptor: a new target for prevention of cold ischemia-reperfusion damage of the rat liver. 979 16

This experiment was designed to determine mechanisms of change in nonadrenergic, noncholinergic (NANC) inhibitory neurons in the ileum after small bowel transplantation (SBT) in the rat and whether nitric oxide (NO) serves as an important NANC inhibitory neurotransmitter in the rat ileum. Eight groups of rats (N > or =8 rats/group) were studied: neurally intact unoperated controls; rats one week after anesthesia and sham celiotomy; and separate groups one and eight weeks after either 40 min of cold ischemia of the jejunoileum, combined jejunal and ileal intestinal transection/reanastomosis, or orthotopic SBT of the entire jejunoileum. Contractile activity was evaluated in full-thickness ileal circular muscle strips under isometric conditions. Spontaneous activity did not differ among groups. In all groups, exogenous NO, NG-monomethyl-L-arginine (L-NMMA, an NO synthase inhibitor), and methylene blue (soluble guanylate cyclase inhibitor) had no effect on spontaneous activity, while 8-bromocyclic guanosine monophosphate (8Br-cGMP) inhibited contractile activity in all groups. Low frequency (2-10 Hz) electrical field stimulation (EFS) inhibited contractile activity only in control and SBT groups; L-NMMA and methylene blue did not alter the response to EFS in any group. These results suggest that each aspect of the SBT procedure, ischemia/reperfusion injury, disruption of enteric neural continuity by intestinal transection, and extrinsic denervation, alter function of enteric ileal inhibitory neurons separately early (one week) after operation. NO, a known inhibitory neurotransmitter in other gut regions, does not affect ileal circular muscle in neurally intact tissue nor mediate functional changes in inhibitory nerve function nor smooth muscle contractility after SBT.
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PMID:Functional changes in nonadrenergic, noncholinergic inhibitory neurons in ileal circular smooth muscle after small bowel transplantation in rats. 982 32

Carbon monoxide (CO) is an endogenously generated gas that may play an important physiological role in the circulation. CO is generated by vascular cells as a byproduct of heme catabolism, in which heme oxygenase (HO) catalyzes the degradation of heme to biliverdin, iron and CO. Two distinct isoforms of HO have been identified in vascular tissue. The HO-2 isoform is constitutively expressed and likely mediates the release of CO under normal physiologic conditions. In contrast, the HO-1 isoform is strongly induced in vascular cells by various stress-associated agents and markedly increases CO synthesis during pathological conditions. The release of CO by vascular cells exerts both paracrine and autocrine effects on vascular smooth muscle cells (SMC) and circulating blood cells. CO regulates blood flow and blood fluidity by inhibiting vasomotor tone, SMC proliferation, and platelet aggregation. These vascular effects of CO are mediated via the activation of soluble guanylate cyclase and the consequent rise in intracellular guanosine 3',5'-cyclic monophosphate levels in target tissues. CO may also play a role in various cardiovascular disorders, including endotoxin shock, ischemia-reperfusion, hypertension, and subarachnoid hemorrhage. This review will focus on the recent progress made in understanding the regulation and function of CO in the vasculature.
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PMID:Carbon monoxide and vascular cell function (review). 985 96

Prostaglandin E(1) (PGE(1)) has cardioprotective effects on the ischemic-reperfused heart. To clarify the mechanisms underlying the protective action of PGE(1) on myocardium, we examined the effect of PGE(1) on the L-type Ca(2+) current (I(Ca)) using single atrial cells from rabbits. PGE(1) did not show a significant effect on basal I(Ca) but inhibited the I(Ca) prestimulated by isoproterenol (Iso, 30 nM). This inhibition was concentration dependent (EC(50) = 0.027 microM). Both sulprostone, a specific PGE receptor subtype (EP(1) and EP(3)) agonist, and 11-deoxy-PGE(1), an EP(3) agonist, inhibited the Iso-stimulated I(Ca), similar to PGE(1). Pretreatment with pertussis toxin (PTX) abolished the PGE(1) inhibition of I(Ca). Both the application of forskolin plus IBMX and intracellular dialysis with 8-bromoadenosine 3',5'-cyclic monophosphate eliminated the effect of PGE(1). PGE(1) did not show any further inhibition of I(Ca) when the effect of Iso was almost fully antagonized by acetylcholine. Methylene blue (guanylate cyclase inhibitor), KT-5823 (cGMP-dependent protein kinase inhibitor), and erythro-9-(2-hydroxy-3-nonyl)adenine (type II phosphodiesterase inhibitor) did not significantly change the inhibitory effect of PGE(1). These findings suggest that 1) PGE(1) inhibits Iso-stimulated I(Ca) by binding to the EP(3) receptor and 2) the PTX-sensitive and cAMP-dependent pathway is involved in the PGE(1) inhibition of I(Ca), but the nitric oxide-cGMP-dependent pathway is not. The PGE(1)-induced antiadrenergic effect shown in this study may contribute to the PGE(1) protection of myocardium against ischemia.
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PMID:EP receptor-mediated inhibition by prostaglandin E(1) of cardiac L-type Ca(2+) current of rabbits. 1051 71

Participation of nitric oxide (NO) and hydroxyl radicals in the pathogenesis of hemodynamic alterations after postischemic recirculation were examined by measuring cerebral blood flow (CBF) and estimating guanylate cyclase activities in arteriolar smooth muscle cells using a reversible 2-h thread occlusion model in rats and an electron microhistochemical technique. In the reversible 2-h ischemia model, guanylate cyclase activity in the arteriolar smooth muscle cells increased at the peak of hyperemia and decreased during postischemic hypoperfusion. Administration of N(omega)-nitro-l-arginine (L-NNA), a NO synthase inhibitor, in this model decreased infarct volume and completely inhibited both hyperemia and guanylate cyclase activation at hyperemia. Administration of 1,2-bis(nicotinamido)-propane (AVS), a free radical scavenger, affected neither CBF nor guanylate cyclase activity during hyperemia despite a significant reduction in infarct volume. Administration of L-NNA and AVS significantly suppressed the decrease in CBF during postischemic hypoperfusion and the effect of AVS was greater than that of L-NNA. Although continuous infusion of sodium nitroprusside (SNP) following postischemic hypoperfusion in the reversible 2-h ischemia rats without treatment with L-NNA and AVS did not alter either CBF or guanylate cyclase activity, it significantly elevated both CBF and guanylate cyclase activities in rats administered L-NNA and AVS. The responses of CBF and guanylate cyclase to SNP were also greater in AVS- than L-NNA-treated rats. These results suggest that a physiological vasodilative mechanism is involved in the induction of postischemic hyperemia through the NO-guanylate cyclase pathway in arteriolar smooth muscle cells. Both NO-related and non-related radicals are involved in the pathogenesis of postischemic delayed hypoperfusion through the loss of arteriolar smooth muscle relaxation capability.
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PMID:Changes in guanylate cyclase activity in arteriolar smooth muscle cells and hemodynamics after ischemia-reperfusion in rats. 1060 36

Peroxynitrite (ONOO(-)) formation during acute reperfusion of the ischemic heart contributes to the poor recovery of mechanical function. As glutathione (GSH) detoxifies ONOO(-), we studied whether it could protect isolated rat hearts subjected to exogenous ONOO(-)or to ischemia-reperfusion. We showed that GSH (300 microm, n=5) abolished the detrimental effect of ONOO(-)(80 microm, n=5) on mechanical function of aerobically perfused hearts. Hearts were subjected to 25 min aerobic perfusion, 20 min global, no-flow ischemia and 30 min reperfusion. GSH (3-300 microm, n=7-12) or saline vehicle (control, n=22) were infused for 10 min prior to ischemia and throughout reperfusion. During reperfusion, GSH caused a concentration-dependent improvement in the recovery of mechanical function, which was not associated with significant changes in the intracellular concentration of GSH. The concentration of dityrosine (a marker of ONOO(-) formation) in the coronary effluent during reperfusion was significantly reduced in GSH-treated hearts. The concentration of myocardial cGMP was significantly elevated by GSH during ischemia and early reperfusion. GSH improves the recovery of myocardial mechanical function after ischemia-reperfusion, an effect which may be related to the detoxification of ONOO(-)by GSH and the stimulation of soluble guanylate cyclase.
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PMID:Glutathione protects against myocardial ischemia-reperfusion injury by detoxifying peroxynitrite. 1096 29

Reactive oxygen species (ROS) hydrogen peroxide (H(2)O(2)) and hypochlorite (HOCl) participate in the pathogenesis of ischemia/reperfusion injury, inflammation, and atherosclerosis. Both NO and ROS are important modulators of vascular tone and architecture and of adhesive interactions between leukocytes, platelets, and vascular endothelium. We studied the effect of H(2)O(2) and HOCl on receptor-dependent (bradykinin [10(-6) mol/L] and ADP [10(-4) mol/L]) and receptor-independent mechanisms (calcium ionophore A23187 [10(-6) mol/L]) of NO production by porcine aortic endothelial cells (ECs). Changes in the level of EC cGMP (the second messenger of NO) were used as a surrogate of NO production. EC cGMP increased 300% in response to bradykinin and A23187 and 200% in response to ADP. Exposure of ECs to H(2)O(2) (50 micromol/L) for 30 minutes significantly impaired cGMP levels in response to ADP, bradykinin, and the receptor-independent NO agonist A23187. In contrast, preincubation with HOCl (50 micromol/L) impaired cGMP production only in response to ADP and bradykinin but not A23187. These concentrations of H(2)O(2) and HOCl did not result in increased EC lethality as assessed by lactate dehydrogenase release. Neither H(2)O(2) nor HOCl affected EC cGMP production in response to NO donor sodium nitroprusside, which suggests that guanylate cyclase is resistant to these oxidants. We also demonstrated that neither H(2)O(2) nor HOCl affects endothelial NO synthase (eNOS) catalytic activity as measured by conversion of L-arginine to L-citrulline in EC homogenates supplemented with eNOS cofactors. The present studies show that H(2)O(2) impairs NO production in response to both receptor-dependent and receptor-independent agonists and that these effects are due, at least in part, to inactivation of eNOS cofactors, whereas HOCl inhibits NO production by interfering with receptor-operated mechanisms at the level of the cell membrane. Concentrations of H(2)O(2) and HOCl used in the present studies have been shown to be generated in vivo during inflammation and ischemia/reperfusion. Therefore, we infer that these effects of H(2)O(2) and HOCl on EC NO production may contribute to disregulated vascular tone and altered leukocyte-EC interactions that occur in vascular injury as a result of those causes in which ROS generation is involved.
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PMID:Effects of the reactive oxygen species hydrogen peroxide and hypochlorite on endothelial nitric oxide production. 1164 2

Nitric oxide has been shown to be involved in the regulation of cerebral blood flow and the consequences of cerebral ischemia. Short-term inhibition of its synthesis induces hypertension and increases the cortical infarct volume in focal ischemia. Our purpose was to investigate the influence of the long-term inhibition of nitric oxide synthase on infarct volume due to middle cerebral artery (MCA) occlusion and on the reactivity of cerebral arteries. Sprague Dawley rats were given N(omega)-nitro-L-arginine methyl ester (L-NAME) for 2 or 6 weeks and compared to untreated normotensive rats and untreated spontaneously hypertensive rats (SHRs). Brain nitric oxide synthase activity was measured by the 14C-L-arginine assay. Arterial blood pressure was measured in each group. Independently, the reactivity of MCA trees was studied in vitro by a perfusion technique. Cortical infarct volume was not significantly modified by either 2-week or 6-week L-NAME treatment, despite induced hypertension, whereas it was significantly higher in SHRs than in normotensive rats. The reactivity of the MCA tree was significantly affected by the treatment with a clearcut time-dependency. Compared to normotensive controls, contractility to noradrenaline and serotonin was reduced, more severely at 6 weeks, and while dilatation to acetylcholine and nitroprusside was moderately reduced at 6 weeks, dilatation to papaverine was then increased. A major difference of treated animals compared to SHRs was the decreased response to 5-hydroxytryptamine. We conclude that infarct expansion may be limited in treated animals by a progressive reduction in cerebral artery response to vasoconstrictory neurotransmitters, concomitant with augmented non-guanylate cyclase dilator responses (cf. papaverine) and some recovery of dilatation to acetylcholine.
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PMID:Effects of chronic L-NAME treatment on rat focal cerebral ischemia and cerebral vasoreactivity. 1166 63


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