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 32 published reports in surgical patients, the preponderance of evidence from standard clinical measures of renal function (BUN and Cr) indicates the absence of renal toxicity following sevoflurane anesthesia. Studies of surgical patients receiving intermediate-duration sevoflurane with high or low fresh gas flow and long-duration sevoflurane with high fresh gas flow included sensitive measures of renal function and/or injury, which also indicate the absence of renal toxicity following sevoflurane anesthesia. Studies of surgical patients receiving long-duration sevoflurane with low fresh gas flow did not include sensitive measures. Seven studies in volunteers are not directly relevant to clinical practice but do raise the issue of whether it is important to apply sensitive measures of renal function and/or injury such as urine concentrations and/or excretion of NAG, beta 2M, alpha 1M, AAP, alpha GST, pi GST, gamma GTP, albumin, protein, and glucose and Cr clearance. Two studies of volunteers receiving prolonged sevoflurane anesthesia with fresh gas flow no greater than 2 L/min concluded that the potential for adverse renal effects of sevoflurane may exist. The other studies of volunteers did not. In 14 published reports of surgical patients in special conditions, the preponderance of evidence from standard clinical measures of renal function indicates the absence of renal toxicity. Studies with sensitive measures have been reported for some conditions where the kidney may be at increased risk (e.g., sevoflurane-induced hypotension, advanced age, and renal insufficiency and failure), are incomplete in others (e.g., hypertension and ischemic heart disease), and are missing in others (e.g., morbid obesity). Studies with sensitive measures of renal function and/or injury are also missing in an important group where the kidney may not be at increased risk--pediatric patients. Studies of other risk conditions, such as temporary ischemia, hemorrhagic hypotension, nephrotoxic antibiotics, kidney transplantation, and diabetes may provide additional information about the renal effects of sevoflurane.
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PMID:Renal effects of sevoflurane during conditions of possible increased risk. 980 93

Intracellular ATP depletion is a hallmark event in ischemic injury. It has been extensively characterized in models of chemical anoxia in vitro. In contrast, the fate of GTP during ischemia remains unknown. We used LLC-PK proximal tubular cells to measure GTP and ATP changes during anoxia. In 45 min, antimycin A decreased ATP and GTP to 8% and 2% of controls, respectively. Ischemia in vivo resulted in comparable reductions in GTP and ATP. After 2 h of recovery, GTP levels in LLC-PK cells increased to 65% while ATP increased to 29%. We also investigated steady-state models of selective ATP or GTP depletion. Combinations of antimycin A and mycophenolic acid selectively reduced GTP to 51% or 25% of control. Similarly, alanosine selectively reduced ATP to 61% or 26% of control. Selective GTP depletion resulted in significant apoptosis. Selective ATP depletion caused mostly necrosis. These models of ATP or GTP depletion can prove useful in dissecting the relative contribution of the two nucleotides to the ischemic phenotype.
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PMID:Modeling ischemia in vitro: selective depletion of adenine and guanine nucleotide pools. 1100 7

RP58866 is a potent antiarrhythmic drug that maintains its antiarrhythmic properties during ischemia. Since interstitial concentrations of adenosine increase during ischemia, we examined the properties of the drug with respect to the muscarinic K+ current (IK(ACh)), with a main emphasis on the adenosine (Ado)-induced current (IK(Ado)). Using different Gi-coupled receptors (M2, A1, sphingolipid), we studied the effect of RP58866 in isolated guinea-pig atrial myocytes by the whole-cell voltage clamp technique. Application of 50 microM RP58866 resulted in complete inhibition of the muscarinic K+ current. Inhibition was observed during activation of IK(ACh) by each of the three receptors. IC50 was approximately 2.0 microM. GTP-gamma-S induced IK(ACh) was reduced by RP58866. The drug was active from the outside only, and its intracellular application via the patch pipet had no inhibitory effect. Despite the structural homologies between inward rectifying K+ channels, the adenosine triphosphate-sensitive K+ current (IK(ATP)) was not inhibited by the compound. It is concluded that muscarinic K+ current is inhibited by RP58866, an inhibition not limited to IK1, Ito, and IKr. High interstitial adenosine concentrations during ischemia are expected to increase the participation of IK(Ado) on repolarization. RP58866-induced inhibition of IK(Ado) would, therefore, be of particular relevance during ischemia. The high sensitivity of IK(Ado) to RP58866 may partially explain the unique properties of the drug toward arrhythmias developing in the ischemic myocardium.
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PMID:Inhibition of muscarinic potassium current by the class III antiarrhythmic drug RP58866 in guinea-pig atrial myocytes. 1113 31

We examined if the adenosine A(1) receptor agonist adenosine amine congener (ADAC, 100 microg/kg i.p.) is neuroprotective in 7-day-old rats subjected to hypoxic ischemia. Brain damage, evaluated as weight deficit and gross morphology, was not affected by ADAC treatment. Nonetheless, ADAC (100 microg/kg i.p.) reduced heart rate by 44% (p<0.0001), indicating that the dose given was pharmacologically active. Adenosine A(1) receptors were determined by [(3)H] 1,3-dipropyl-8-cyclopentylxanthine (DPCPX)-binding and levels were 23% of the adult levels. GTP did not affect [(3)H] DPCPX-binding in the cerebral cortex at postnatal day 7 whereas there was strong enhancement of [(3)H] DPCPX-binding in the heart. This suggested a poor G-protein coupling at postnatal day 7 in the brain, which also was confirmed using GTP [gamma-(35)S]-binding in the presence of an adenosine A(1) receptor agonist. Thus, the lack of a neuroprotective effect of ADAC may be explained by the fact that adenosine A(1) receptors are not part of a functional unit in the 7-day-old rat brain.
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PMID:Adenosine A(1) receptor agonism in the immature rat brain and heart. 1152 43

Ischemic injury to the kidney is characterized in part by nucleotide depletion and tubular cell death in the form of necrosis or apoptosis. Recently, we linked anoxia-induced apoptosis in renal cell cultures specifically to the depletion of GTP. We therefore hypothesized that enhancing GTP repletion in vivo might protect function by reducing apoptosis in postischemic tubules. Male C57 black mice (the "I" group of animals) underwent bilateral renal artery clamp for 32 minutes to induce ischemia and then received either normal saline ("NS") or guanosine ("G"). After 1 hour of reperfusion, renal GTP levels in NS/I were reduced to nearly half of those in sham operated mice, whereas these levels were nearly unchanged in G/I mice. Morphologic examination of tubular injury revealed no significant differences between the two groups. However, there was a significant reduction in the number of apoptotic tubular cells in the medulla in the G/I group as compared with the NS/I group. At 24 hours, creatinine was significantly elevated in the NS/I group, compared to the G/I group. We conclude that guanosine protects against renal ischemic injury by replenishing GTP stores and preventing tubular apoptosis.
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PMID:Guanosine supplementation reduces apoptosis and protects renal function in the setting of ischemic injury. 1169 71

This study tested the hypothesis that classic ischemic preconditioning can cause changes in gene expression patterns in the rabbit heart, assessed by gene array technology. Open-chest rabbits were randomly assigned to sham-operated and ischemically preconditioned groups. The sham-operated group received 5 hours and 20 minutes of no intervention, while the ischemically preconditioned group was subjected to two episodes of preconditioning ischemia (5 minutes each) separated by 5 minutes of reperfusion, followed by an additional 5 hours and 5 minutes of reperfusion. (33)P-labeled cDNA from the sham-operated hearts and the nonischemic and preconditioned areas of the ischemically preconditioned group was hybridized to filters spotted with 18,376 human cDNA clones. Altogether, 35 genes with significantly altered expression patterns were discovered. In the preconditioned area, genes for MAPKAP kinase 3 and cathepsin G were up-regulated. In the nonischemic area, genes for GTP exchange factor, Na(+), K(+)-ATPase, Zn finger protein 35, a representative of the CEA family, cytochrome c oxidase, mitogen-responsive phosphoprotein, and Ran-binding protein were up-regulated. None of the identified genes had been previously reported to be involved in ischemic preconditioning.
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PMID:Gene activity changes in ischemically preconditioned rabbit heart gene: discovery array study. 1197 36

Deletion of the major adenylate kinase AK1 isoform, which catalyzes adenine nucleotide exchange, disrupts cellular energetic economy and compromises metabolic signal transduction. However, the consequences of deleting the AK1 gene on cardiac energetic dynamics and performance in the setting of ischemia-reperfusion have not been determined. Here, at the onset of ischemia, AK1 knockout mice hearts displayed accelerated loss of contractile force compared with wild-type controls, indicating reduced tolerance to ischemic stress. On reperfusion, AK1 knockout hearts demonstrated reduced nucleotide salvage, resulting in lower ATP, GTP, ADP, and GDP levels and an altered metabolic steady state associated with diminished ATP-to-P(i) and creatine phosphate-to-P(i) ratios. Postischemic AK1 knockout hearts maintained approximately 40% of beta-phosphoryl turnover, suggesting increased phosphotransfer flux through remaining adenylate kinase isoforms. This was associated with sustained creatine kinase flux and elevated cellular glucose-6-phosphate levels as the cellular energetic system adapted to deletion of AK1. Such metabolic rearrangements, along with sustained ATP-to-ADP ratio and total ATP turnover rate, maintained postischemic contractile recovery of AK1 knockout hearts at wild-type levels. Thus deletion of the AK1 gene reveals that adenylate kinase phosphotransfer supports myocardial function on initiation of ischemic stress and safeguards intracellular nucleotide pools in postischemic recovery.
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PMID:Adenylate kinase AK1 knockout heart: energetics and functional performance under ischemia-reperfusion. 1212 27

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

Ischemic injury to the kidney is characterized in part by nucleotide depletion and tubular cell death in the form of necrosis or apoptosis. GTP depletion was recently identified as an important inducer of apoptosis during chemical anoxia in vitro and ischemic injury in vivo. It has also been shown that GTP salvage with guanosine prevented apoptosis and protected function. This study investigates the role of p53 in mediating the apoptotic response to GTP depletion. Male Sprague-Dawley rats underwent bilateral renal artery clamp for 30 min followed by reperfusion. p53 protein levels increased significantly in the medulla over 24 h post-ischemia. The provision of guanosine inhibited the increase in p53. Pifithrin-alpha, a specific inhibitor of p53, mimicked the effects of guanosine. It had no effect on necrosis, yet it prevented apoptosis and protected renal function. Pifithrin-alpha was protective when given up to 14 h after the ischemic insult. The effects of pifithrin-alpha on p53 included inhibition of transcriptional activation of downstream p53 targets like p21 and Bax and inhibition of p53 translocation to the mitochondria. Similar results were obtained in cultured renal tubular cells. It is concluded that p53 is an important mediator of apoptosis during states of GTP depletion. Inhibitors of p53 should be considered in the treatment of ischemic renal injury.
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PMID:P53 mediates the apoptotic response to GTP depletion after renal ischemia-reperfusion: protective role of a p53 inhibitor. 1250 60

Rho GTPases are critical for actin cytoskeletal regulation, and alterations in their activity may contribute to altered cytoskeletal organization that characterizes many pathological conditions, including ischemia. G protein activity is a function of the ratio of GTP-bound (active) to GDP-bound (inactive) protein, but the effect of altered energy metabolism on Rho protein activity has not been determined. We used antimycin A and substrate depletion to induce depletion of intracellular ATP and GTP in the kidney proximal tubule cell line LLC-PK10 and measured the activity of RhoA, Rac1, and Cdc42 with GTPase effector binding domains fused to glutathione S-transferase. RhoA activity decreased in parallel with the concentration of ATP and GTP during depletion, so that by 60 min there was no detectable RhoA-GTP, and recovered rapidly when cells were returned to normal culture conditions. Dissociation of the membrane-actin linker ezrin, a target of RhoA signaling, from the cytoskeletal fraction paralleled the decrease in RhoA activity and was augmented by treatment with the Rho kinase inhibitor Y27632. The activity of Cdc42 did not decrease significantly during depletion or recovery. Rac1 activity decreased moderately to a minimum at 30 min of depletion but then increased from 30 to 90 min of depletion, even as ATP and GTP levels continued to fall. Our data are consistent with a principal role for RhoA in cytoskeletal reorganization during ischemia and demonstrate that the activity of Rho GTPases can be maintained even at low GTP concentrations.
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PMID:Rho GTPases show differential sensitivity to nucleotide triphosphate depletion in a model of ischemic cell injury. 1262 Aug 11


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