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)

Ischemia/reperfusion-induced acute renal failure is a common clinical problem associated with a high morbidity and mortality. Upon hypoxic injury, the depletion of ATP causes mitochondrial dysfunction, and accumulation of intracellular sodium, calcium and reactive oxygen species. Subsequently, multiple enzyme systems including proteases, nitric oxide synthases, phospholipases and endonuclease are activated and responsible for cytoskeleton disruption, membrane damage, and DNA degradation, and eventually cell death. Ischemia/reperfusion injury also activates complement, cytokines, and chemokines, which are cytotoxic themselves, but also attract leukocytes into the ischemic area to cause further damage. The vascular endothelial cell injury and dysfunction prolong ischemia and induce vascular congestion, edema, and further infiltration of inflammatory cells. Many players in renal ischemia/reperfusion injury and their mechanisms have been investigated using genetically manipulated mouse models. In this review, we focus on the information gathered from these studies. Deficiency of the Na/Ca exchanger, inducible nitric oxide synthase, Caspase-1, A3 adenosine receptor, C3, C5, C6, Factor B, or midkine protects the kidney against I/R injury. Conversely, deficiency of the interleukin-1 receptor, osteopontin, C4, or recombination activation gene-1 is not protective, while the absence of adrenomedullin or endothelin receptor B delays the recovery of ischemia/reperfusion injury. The knowledge obtained from these studies provides new direction for designing potential therapeutic agents for treating ischemia/reperfusion injury.
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PMID:Pathogenesis of renal ischemia/reperfusion injury: lessons from knockout mice. 1462 25

Apoptosis has been described in various models of ischemia-reperfusion (IR) injury, including lung transplantation. A3 adenosine receptor (AR) has been linked to a variety of apoptotic processes. The effect of A3AR activation on lung injury and apoptosis, following IR, has not been reported to date. In a spontaneously breathing cat model, in which the left lower lobe of the lung was isolated and subjected to 2 h of ischemia and 3 h of reperfusion, we tested the effect of IB-MECA, a selective A3AR agonist, on lung apoptosis and injury. Significant increase in the extent of apoptosis was observed following lung reperfusion. IB-MECA, administered before IR, and before or with reperfusion, markedly (p < 0.01) attenuated indices of injury and apoptosis including the percentage of injured alveoli, wet/dry weight ratio, myeloperoxidase activity, in situ terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL) positive cells, and caspase 3 activity and expression. The protective effects of IB-MECA were completely blocked by pretreatment with the selective A3AR antagonist MRS-1191. In summary, even when given after the onset of ischemia, the A3AR agonist IB-MECA conferred a powerful protection against reperfusion lung injury, which was associated with decreased apoptosis. This suggests a potentially important role for A3AR in lung IR injury.
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PMID:Activation of A3 adenosine receptor provides lung protection against ischemia-reperfusion injury associated with reduction in apoptosis. 1557 95

Activation of the A2A adenosine receptor (A(2A)R) during reperfusion of various tissues has been found to markedly reduce ischemia-reperfusion injury. In this study, we used bone marrow transplantation (BMT) to create chimeric mice that either selectively lack or selectively express the A(2A)R on bone marrow-derived cells. Bolus i.p. injection of the selective A2A agonist, 4-[3-[6-amino-9-(5-cyclopropylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl]-piperidine-1-carboxylic acid methyl ester (ATL313; 3 microg/kg), at the time of reperfusion protects wild-type (wt) mice from liver ischemia-reperfusion injury. ATL313 also protects wt/wt (donor/recipient BMT mouse chimera) and wt/knockout chimera but produces modest protection of knockout/wt chimera as assessed by alanine aminotransferase activity, induction of cytokine transcripts (RANTES, IFN-gamma-inducible protein-10, IL-1alpha, IL-1-beta, IL-1Ralpha, IL-18, IL-6, and IFN-gamma), or histological criteria. ATL313, which is highly selective for the A(2A)R, produces more liver protection of chimeric BMT mice than 4-[3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl]-cyclohexanecarboxylic acid methyl ester, which is rapidly metabolized in mice to produce 4-[3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl]-cyclohexanecarboxylic acid, which has similar affinity for the A(2A)R and the proinflammatory A3 adenosine receptor. GFP chimera mice were created to show that vascular endothelial cells in the injured liver do not account for liver protection because they are not derived by transdifferentiation of bone marrow precursors. The data suggest that activation of the A(2A)R on bone marrow-derived cells is primarily responsible for protecting the liver from reperfusion injury.
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PMID:A2A adenosine receptors on bone marrow-derived cells protect liver from ischemia-reperfusion injury. 1581 35

The A3 adenosine receptor (A3AR) is attributed with multiple beneficial actions in ischemic-reperfused myocardium, including modulation of oncotic and apoptotic cell death and enhancement of contractile function. Additionally, the A3AR may attenuate vascular dysfunction and improve long-term outcome from myocardial insult (modulating hypertrophy and angiogenesis). Available evidence indicates that this receptor sub-type is minimally activated by endogenous adenosine during ischemia (A3AR antagonists exerting no effects on ischemic outcome), and is thus amenable to activation with exogenous agonists. Protected phenotypes arise with both pre- and post-ischemic treatment with A3AR agonists, and transient A3AR agonism also triggers early and delayed preconditioned states. The molecular basis for the varied protective actions of the A3AR remains poorly defined, and may well vary between species (e.g. rodent vs. human) and protective responses (e.g. acute vs. delayed protection). Nonetheless, A3ARs may be more promising as therapeutic "anti-ischemic" targets compared with other adenosine receptor subtypes, since A3AR agonists elicit fewer and less significant side-effects. This review addresses current knowledge and controversy regarding the protective actions (and associated signaling) of A3ARs in ischemic-reperfused heart.
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PMID:A3 adenosine receptor-mediated protection of the ischemic heart. 1592 60

This study evaluated the ability of A1 and A3 adenosine receptor (AR) agonism, and A1, A2A, A2B and A3AR antagonism (revealing "intrinsic" responses), to modify post-ischemic coronary dysfunction in mouse heart. Vascular function was assessed before and after 20 min global ischemia and 30-45 min reperfusion in Langendorff perfused C57/Bl6 mouse hearts. Ischemic insult impaired coronary sensitivity to the endothelial-dependent dilators ADP (pEC50=6.8+/-0.1 vs. 7.6+/-0.1, non-ischemic) and acetylcholine (pEC50=6.1+/-0.1 vs. 7.3+/-0.1 in non-ischemic), and for the mixed endothelial-dependent/independent dilator 2-chloroadenosine (pEC50=7.5+/-0.1 vs. 8.4+/-0.1, non-ischemic). Endothelium-independent dilation in response to nitroprusside was unaltered (pEC50=7.0+/-0.1 vs. 7.1+/-0.1 in non-ischemic). Pre-treatment with a selective A1AR agonist (50 nM CHA) failed to modify coronary dysfunction, whereas A1AR antagonism (200 nM DPCPX) worsened the effects of I/R (2-chloroadenosine pEC50=6.9+/-0.1). Conversely, A3AR agonism (100 nM Cl-IB-MECA) did reduce effects of I/R (pEC50s=8.0+/-0.1 and 7.3+/-0.1 for 2-chloroadenosine and ADP, respectively), whereas antagonism (100 nM MRS1220) was without effect. While A2AAR agonism could not be assessed (due to pronounced vasodilatation), A2AAR antagonism (100 nM SCH58261) was found to exert no effect, and antagonism of A2BARs (50 nM MRS1754) was also ineffective. The protective actions of A3AR agonism were also manifest as improved reactive hyperemic responses. Interestingly, post-ischemic coronary dysfunction was also limited by: Na+-H+ exchange (NHE) inhibition with 10 or 50 microM BIIB-513 (2-chloroadenosine pEC50s=7.8+/-0.1, either dose), an effect not additive with A3AR agonism; Ca2+ antagonism with 0.3 microM verapamil (2-chloroadenosine pEC50=7.9+/-0.1); and Ca2+ desensitization with 5 mM BDM (2-chloroadenosine pEC50=7.8+/-0.1). In contrast, endothelin antagonism (200 nM PD142893) and anti-oxidant therapy (300 microM MPG+150 U/ml SOD+600 U/ml catalase) were ineffective. Our data collectively confirm that ischemia selectively impairs endothelial function and reactive hyperemia independently of blood cells. Vascular injury is intrinsically limited by endogenous (but not exogenous) activation of A1ARs, whereas exogenous A3AR activation further limits dysfunction (improving post-ischemic vasoregulation). Finally, findings suggest this form of post-ischemic coronary injury is unrelated to endothelin or oxidant stress, but may involve modulation of Ca2+ overload and/or related ionic perturbations.
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PMID:Adenosine receptor-mediated coronary vascular protection in post-ischemic mouse heart. 1630 Jul 99

Adenosine receptors (ARs) are a four-member subfamily of G protein-coupled receptors and are major targets of caffeine and theophylline. There are four subtypes of ARs, designated as A1, A2A, A2B and A3. Selective agonists are now available for all four subtypes. Over a dozen of these selective agonists are now in clinical trials for various conditions, although none has received regulatory approval except for the endogenous AR agonist adenosine itself. A1AR agonists are in clinical trials for cardiac arrhythmias and neuropathic pain. A2AAR agonists are now in trials for myocardial perfusion imaging and as anti-inflammatory agents. A2BAR agonists are under preclinical scrutiny for potential treatment of cardiac ischemia. A3AR agonists are in clinical trials for the treatment of rheumatoid arthritis and colorectal cancer. The present review will mainly cover the agonists that are presently in clinical trials for various conditions and only a brief introduction will be given to major chemical classes of AR agonists presently under investigation.
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PMID:Emerging adenosine receptor agonists. 1787 74

1 Limiting the impact of ischemia reperfusion-related cell death is of vital importance given the enormous figures of heart related mortality in the world. 2 Coronary heart disease (CHD) is responsible for over 100,000 deaths in the UK each year, and is the most common cause of premature death in the UK and as a whole it is estimated that there are just over 1.5 million men, and 1.1 million women, who have suffered CHD in the form of either angina or myocardial infarction (http://www.heartstats.org). 3 In patients undergoing standard clinical reperfusion treatment today such as thrombolysis, percutaneous coronary angioplasty (primary PCTA), and bypass surgery, there remains an underscored need for novel therapies and strategies to reduce post-ischemic infarct size. 4 This review focuses on some of the intracellular signalling pathways that have been proposed to be coupled to A3 adenosine receptors in order to reduce post-ischemic infarct size, in particular the role of nitric oxide in A3 adenosine receptor-mediated cardioprotection is discussed.
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PMID:The role of nitric oxide in A3 adenosine receptor-mediated cardioprotection. 1956 49

Adenosine plays an important part in the cardiac response to ischemia and reperfusion. The human adenosine receptor A3 (A3R), along with other adenosine receptors, is involved in mediation of those effects. The aim of the study was to ascertain whether the nonsynonymous single-nucleotide polymorphism (SNP) I248L (reference SNP ID: rs35511654) located in the A3R gene is associated with coronary heart disease (CHD). DNA samples from 683 individuals with CHD and from 826 control subjects selected from the Latvian Genome Database were successfully screened for rs35511654 using the TaqMan SNP Genotyping Assay. We observed a significantly decreased frequency of the rs35511654 C allele in a group of CHD patients compared with that in controls (p = 0.009). The association remained significant after adjustment for age, sex, and other nongenetic factors (p = 0.02). These results suggest that A allele of rs35511654 may predispose to CHD.
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PMID:A nonsynonymous variant I248L of the adenosine A3 receptor is associated with coronary heart disease in a Latvian population. 2167 73

Vascular dysfunction importantly contributes to mortality and morbidity in various cardiac and metabolic diseases. Among endogenous molecules regulating vascular tone is adenosine, with the adenosine A3 receptor (A3AR) exerting cardioprotective properties in ischemia and reperfusion. However, overexpression of A3AR is suggested to result in vascular dysfunction and inflammation. The leukocyte enzyme myeloperoxidase (MPO) is an important modulator of vascular function with nitric oxide-consuming and proinflammatory properties. Increased MPO plasma levels are observed in patients with cardiovascular disorders like heart failure, acute coronary syndromes, and arrhythmias. Given that vascular dysfunction and inflammation are also hallmarks of diabetes, the role of MPO in adenosine-dependent vasomotor function was investigated in a murine model of diabetes mellitus. Wild-type (WT) and MPO-deficient (Mpo) mice were treated with Streptozotocin (STZ), which induced an increase of MPO plasma levels in WT mice and led to enhanced aortic superoxide generation as assessed by dihydroethidium staining in STZ-treated WT mice as compared with controls. The vasoconstriction of aortic segments in response to the A3AR agonist Cl-IB-MECA (2-Chloro-N6-(3-iodobenzyl)-N-methyl-5-carbamoyladenosine) as determined by isometric force measurements was augmented in diabetic WT as compared with diabetic Mpo mice. Moreover, A3AR protein expression was enhanced in STZ-treated mice but was attenuated by MPO deficiency. The current data reveal an MPO-mediated increase of vascular A3AR expression under diabetic conditions, which leads to enhanced vasoconstriction in response to A3AR agonists and discloses an additional mechanism of MPO-mediated vascular dysfunction.
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PMID:Increased A3AR-dependent vasoconstriction in diabetic mice is promoted by myeloperoxidase. 2500 Apr 78

Adenosine is a ubiquitous, endogenous purine involved in a variety of physiological and pathophysiological regulatory mechanisms. Adenosine has been proposed as an endogenous antiarrhythmic substance to prevent hypoxia/ischemia-induced arrhythmias. Adenosine (and its precursor, ATP) has been used in the therapy of various cardiac arrhythmias over the past six decades. Its primary indication is treatment of paroxysmal supraventricular tachycardia, but it can be effective in other forms of supraventricular and ventricular arrhythmias, like sinus node reentry based tachycardia, triggered atrial tachycardia, atrioventricular nodal reentry tachycardia, or ventricular tachycardia based on a cAMP-mediated triggered activity. The main advantage is the rapid onset and the short half life (1- 10 sec). Adenosine exerts its antiarrhythmic actions by activation of A1 adenosine receptors located in the sinoatrial and atrioventricular nodes, as well as in activated ventricular myocardium. However, adenosine can also elicit A2A, A2B and A3 adenosine receptor-mediated global side reactions (flushing, dyspnea, chest discomfort), but it may display also proarrhythmic actions mediated by primarily A1 adenosine receptors (e.g. bradyarrhythmia or atrial fibrillation). To avoid the non-specific global adverse reactions, A1 adenosine receptor- selective full agonists (tecadenoson, selodenoson, trabodenoson) have been developed, which agents are currently under clinical trial. During long-term administration with orthosteric agonists, adenosine receptors can be internalized and desensitized. To avoid desensitization, proarrhythmic actions, or global adverse reactions, partial A1 adenosine receptor agonists, like CVT-2759, were developed. In addition, the pharmacologically "silent" site- and event specific adenosinergic drugs, such as adenosine regulating agents and allosteric modulators, might provide attractive opportunity to increase the effectiveness of beneficial actions of adenosine and avoid the adverse reactions.
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PMID:The Janus face of adenosine: antiarrhythmic and proarrhythmic actions. 2535 87


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