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)

Olmesartan is a selective angiotensin II type 1 receptor (AT1) antagonist. In pentobarbital-anesthetized open-chest dogs, ischemia/reperfusion was induced by ligating the left anterior descending coronary artery for 20 min and releasing it for 60 min, respectively. The myocardial contraction in the ischemic area decreased and returned towards its pre-ischemic level during reperfusion but incompletely. Olmesartan improved the recovery of myocardial contraction during reperfusion associated with restoration of myocardial ATP. Angiotensin II repelled by AT1 receptors occupied by olmesartan can reach and stimulate the angiotensin II type 2 (AT2) receptors, resulting in some beneficial effects on the ischemic myocardium. In fact, AT2 receptor mRNA was found in the adult dog myocardium. In addition, the plasma level of angiotensin II was significantly increased by olmesartan. PD123319, a selective AT2 receptor antagonist, however, did not modify the effect of olmesartan on the cardiac contraction. The hypertensive response to exogenous angiotensin II was completely inhibited by olmesartan, whereas PD123319 did not abolish the effect of olmesartan. In conclusion, olmesartan protects the ischemic/reperfused heart against ischemic injury through inhibition of AT1 receptors but not indirect activation of AT2 receptors.
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PMID:Improvement of stunned myocardium in dogs with olmesartan, an angiotensin II type 1 receptor antagonist, is independent of type 2 receptors. 1843 61

The possibility of a direct mitochondrial action of Na(+)/H(+) exchanger-1 (NHE-1) inhibitors decreasing reactive oxygen species (ROS) production was assessed in cat myocardium. Angiotensin II and endothelin-1 induced an NADPH oxidase (NOX)-dependent increase in anion superoxide (O(2)(-)) production detected by chemiluminescence. Three different NHE-1 inhibitors [cariporide, BIIB-723, and EMD-87580] with no ROS scavenger activity prevented this increase. The mitochondria appeared to be the source of the NOX-dependent ROS released by the "ROS-induced ROS release mechanism" that was blunted by the mitochondrial ATP-sensitive potassium channel blockers 5-hydroxydecanoate and glibenclamide, inhibition of complex I of the electron transport chain with rotenone, and inhibition of the permeability transition pore (MPTP) by cyclosporin A. Cariporide also prevented O(2)(-) production induced by the opening of mK(ATP) with diazoxide. Ca(2+)-induced swelling was evaluated in isolated mitochondria as an indicator of MPTP formation. Cariporide decreased mitochondrial swelling to the same extent as cyclosporin A and bongkrekic acid, confirming its direct mitochondrial action. Increased O(2)(-) production, as expected, stimulated ERK1/2 and p90 ribosomal S6 kinase phosphorylation. This was also prevented by cariporide, giving additional support to the existence of a direct mitochondrial action of NHE-1 inhibitors in preventing ROS release. In conclusion, we report a mitochondrial action of NHE-1 inhibitors that should lead us to revisit or reinterpret previous landmark observations about their beneficial effect in several cardiac diseases, such as ischemia-reperfusion injury and cardiac hypertrophy and failure. Further studies are needed to clarify the precise mechanism and site of action of these drugs in blunting MPTP formation and ROS release.
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PMID:Na+/H+ exchanger-1 inhibitors decrease myocardial superoxide production via direct mitochondrial action. 1880 63

Pharmacological inhibition of the renin-angiotensin-aldosteron system (RAAS) constitutes a cornerstone strategy in the management of patients with chronic nephropathies with proteinuria and with chronic renal failure. Angiotensin converting enzyme inhibitors (ACEI) as well as angiotensin II subtype 1 receptor antagonists have been shown to decrease proteinuria, reduce the local renal inflammatory processes and slow the progression of renal insufficiency. Despite recent progress, there is still no optimal therapy that would stop progression of renal disease. May be pentoxifilline (PTF)--the old medication which is still used to treat peripheral vascular disease and brain ischemia will be the new adjunct to RAAS blockade. In addition, PTF has been shown to decrease the production of pro-inflammatory cytokines and reactive oxygen species. PTF therapy may improve the hemoglobin response in patients with previously rh-EPO resistant anemia in renal failure. This may occur due to inhibition of proinflammatory cytokine production. Probably in the next few years we will get answer to the question of PTF role in nephrology.
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PMID:[Pentoxifylline old drug or new hope for nephrology?]. 1900 36

VENTRICULAR ARRHYTHMIAS: Different factors--like hypertrophy, fibrosis, ischemia and apoptosis increase the risk of ventricular arrhythmias and sudden arrhythmic death. ACE inhibitors and Angiotensin receptor antagonists offer a curative therapeutic approach. Beta-blocker are strongly recommended. Amiodarone may be used for symptomatic arrhythmia suppression--but with no proven favourable prognostic effect. The use of class-1 antiarrhythmic drugs is obsolete in the presence of left ventricular hypertrophy and heart failure. Implantable cardioverter/defibrillators (ICD) have been proven to have a positive effect on survival in secondary and primary prevention of sudden cardiac death, and so has cardiac synchronization in severe cardiac dysfunction and widened QRS complex. Atrial fibrillation (AF): Arterial hypertension represents the main risk factor for AF. Patients' age, left ventricular hypertrophy, left atrial dilatation and angiotensin-II activation play an important role in the induction and maintenance of AF. Angiotensin-receptor and beta-blockers seem to be efficacious in AF suppression and also on the regression of hypertrophy. The use of antiarrhythmic agents (AA) is limited because of their relatively low long-term efficacy and pro-arrhythmia properties. Best results may be achieved with class 1C AA drugs in patients with no or minimal structural heart disease. In all other cases amiodarone is suitable but is limited by its side effects. In patients with no or only a few symptoms rate control may be sufficient, but if there are symptoms interventional left atrial ablation of pulmonary veins should be attempted as a real curative strategy.
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PMID:[Arterial hypertension and cardiac arrhythmias]. 1908 3

Angiotensin-(1-7) [Ang-(1-7)] is a vasodilator peptide with cardiac and vascular protective properties. We examined the influence of Ang-(1-7), both endogenous and after chronic treatment with the peptide (576microg/(kgday)), on ischemia/reperfusion (I/R)-induced cardiac dysfunction in streptozotocin-treated spontaneously hypertensive rats (diabetic SHR). In isolated perfused hearts, recovery of left ventricular function from 40min of global ischemia was improved significantly in Ang-(1-7)- or captopril-treated diabetic SHR and worsened in animals treated with A779, an Ang-(1-7) receptor (AT((1-7))) antagonist. The beneficial effect of captopril on cardiac recovery was reduced when co-administered with A779. Cardiac NF-kappaB activity appears to be higher in diabetic SHR and treatment with Ang-(1-7) or captopril decreased NF-kappaB activity in diabetic SHR, an effect partially reversed by co-administration of A779. Real-time PCR-based gene array analysis of cardiac tissue revealed that Ang-(1-7) or captopril treatment may reduce expression of several genes of inflammation involved in the NF-kappaB signalling pathway. The data provide for the first time a role for endogenous Ang-(1-7) as well as confirmation that exogenous treatment with the peptide produces cardioprotection. Whether potential anti-inflammatory and transcriptional factor changes are directly linked to the cardioprotection produced by Ang-(1-7) in diabetic SHR remains to be determined.
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PMID:Endogenous angiotensin-(1-7) reduces cardiac ischemia-induced dysfunction in diabetic hypertensive rats. 1916 39

Toll-like receptor 4 (TLR4) activation has been implicated in the pathogenesis of myocardial ischemia/reperfusion (I/R) injury. The activated TLR4 is capable of activating a variety of proinflammatory mediators, such as tumor necrosis factor-a (TNF-a) and interleukin-6 (IL-6). Valsartan as a kind of Angiotensin II type 1 receptor blockers is gradually used for the treatment of ischemic heart disease depending on its anti-inflammation function. Therefore, we hypothesized that valsartan protects against myocardial I/R injury by suppressing TLR4 activation. We constructed the rat model of myocardial I/R injury. The rats were pretreated with valsartan for 2 weeks, and then subjected to 30 min ischemia and 2 h reperfusion. TLR4 and Nuclear factor kappa-B (NF-kappaB) levels were detected by quantitative real-time PCR and western blot. In order to evaluate myocardial damage, the myocardial infarct size, histopathologic changes, and the release of myocardial enzymes, proinflammation cytokines and Angiotensin II were analyzed by triphenyl tetrazolium chloride (TTC) staining, light microscopy, and enzyme-linked immunosorbent assay (ELISA), respectively. Valsartan preconditioning inhibited TLR4 and NF-kappaB expressions concomitant with an improvement in myocardial injury, such as smaller infarct size, fewer release of myocardial enzymes, and proinflammation mediators. These findings suggest that valsartan plays a pivotal role in the protective effects on myocardial I/R injury. This protection mechanism is possibly due to its anti-inflammation function via TLR4/NF-kappaB signaling pathway.
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PMID:Valsartan preconditioning protects against myocardial ischemia-reperfusion injury through TLR4/NF-kappaB signaling pathway. 1937 Mar 15

Angiotensin (Ang) II mediates pathophysiologial changes in the kidney. Ang-(1-7) by interacting with the G protein-coupled receptor Mas may also have important biological activities.In this study, renal deficiency for Mas diminished renal damage in models of renal insufficiency as unilateral ureteral obstruction and ischemia/reperfusion injury while the infusion of Ang-(1-7) to wild-type mice pronounced the pathological outcome by aggravating the inflammatory response. Mas deficiency inhibited NF-kappaB activation and thus the elevation of inflammation-stimulating cytokines, while Ang-(1-7) infusion had proinflammatory properties in experimental models of renal failure as well as under basal conditions. The Ang-(1-7)-mediated NF-kappaB activation was Mas dependent but did not involve Ang II receptors. Therefore, the blockade of the NF-kappaB-activating properties of the receptor Mas could be a new strategy in the therapy of failing kidney.
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PMID:Angiotensin-(1-7) and the g protein-coupled receptor MAS are key players in renal inflammation. 1940 5

Heart failure (HF) is more prevalent and evolves more rapidly in patients with renal failure (RF). Renal failure not only produces myocardial damage, but also induces the development of clinical heart failure thus making the treatment of these patients more difficult. The incidence of HF in patients with RF is around 15%. Renal function in patients with RF is lower than in the general population. This is true for patients with preserved and depressed left ventricular ejection fraction (LVEF). HF mortality increases 30% for every 1-mg/dL increase in creatinine and renal function should always be considered when assessing the cardiovascular risk and therapeutic alternatives of cardiovascular patients. Angiotensin converting enzyme inhibitors, Angiotensin receptor blockers and aldosterone blockers may cause acute renal failure and serum creatinine and potassium should be closely monitored. Chronic RF is a human model of accelerated atherosclerosis. It induces a rapid progression of coronary atherosclerosis and make atherosclerotic plaques more vulnerable to acute coronary syndromes (ACS) because of coagulation changes inherent to RF. Ischemia is also more frequent due to the imbalance between oxygen requirements and supplies. Chronic RF is associated with a worse outcome in patients with ACS and increases the risk of bleeding, and is associated with a higher mortality in patients under surgical or percutaneous coronary revascularization. Of the patients treated with an interventional coronary procedure (ICP), 3,3% suffer acute RF. Saline administration at a dose of 1 ml/kg/h for 12 hours before and 12 hours after ICP prevents the development of acute RF. Although the role of N-acetylcysteine is under discussion, taking into account the favourable risk profile of this drug, it seems reasonable to administer N-acetylcysteine in addition to saline administration. In ACS patients with severe RF, the risk of severe bleeding depends upon the anticoagulation regimen, increasing particularly when unfractionated heparin is used in combination with GP IIb/IIIa inhibitors.
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PMID:[Kidney disease: therapeutic implications in heart failure and coronary heart disease]. 1946 Apr 81

Impaired skeletal muscle energetic participates in peripheral arterial disease (PAD) patient's morbidity and mortality. Angiotensin converting enzyme inhibition (ACEi), cornerstone for pharmacologic risk factor management in PAD patients, might also be interesting by protecting skeletal muscle energetic. We therefore determined whether chronic ACEi might reduce ischemia-induced mitochondrial respiratory chain dysfunction in the frequent setting of hindlimb ischemia-reperfusion. Ischemic legs of rats submitted to 5 h ischemia induced by a rubber band tourniquet applied on the root of the hindlimb followed by reperfusion without (IR, n = 11) or after ACEi (n = 14; captopril 40 mg/kg per day during 28 days before surgery) were studied and compared to that of sham-operated animals (n = 11). The effect of ACEi on the non-ischemic contralateral leg was also determined in the ACEi group. Maximal oxidative capacities (V(max)) and complexes I, II and IV activities of the mitochondrial respiratory chain of the gastrocnemius muscle were determined using glutamate-malate, succinate and TMPD-ascorbate substrates. Arterial blood pressure was significantly decreased after ACEi (124 +/- 2.8 vs. 108 +/- 4.19 mmHg; P = 0.01). Ischemia-reperfusion reduced V(max) (4.4 +/- 0.4 vs. 8.7 +/- 0.5 micromol O2/min/g dry weight, -49%, P < 0.001), affecting mitochondrial complexes I, II and IV activities. ACEi failed to modulate ischemia-induced dysfunction (V(max) 5.1 +/- 0.7 micromol O2/min/g dry weight) or the non-ischemic contralateral muscle respiratory rate. Ischemia-reperfusion significantly impaired the mitochondrial respiratory chain I, II and IV complexes of skeletal muscle. Pharmacologic pre-treatment with ACEi did not prevent or increase such alterations. Further studies might be useful to improve the pharmacologic conditioning of PAD patients needing arterial revascularization.
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PMID:Effect of chronic pre-treatment with angiotensin converting enzyme inhibition on skeletal muscle mitochondrial recovery after ischemia/reperfusion. 1968 81

Angiotensin-(1-7), a biologically active peptide of the renin-angiotensin system, is cardioprotective following ischemia/reperfusion and reduces cardiac hypertrophy. A recently discovered homolog of angiotensin converting enzyme (ACE), ACE2, is present in the heart and synthesizes angiotensin-(1-7) from angiotensin II. Cardiac ACE2 is elevated following inhibition of Ang II subtype 1 (AT(1)) receptors or blockade of angiotensin II production, suggesting that angiotensin-(1-7) plays a role in the beneficial effects of AT(1) receptor antagonists and ACE inhibitors in the heart. An increase in ACE2 activity and the production of angiotensin-(1-7) may thus represent a novel therapy for heart failure following myocardial infarction.
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PMID:Cardioprotective role for angiotensin-(1-7) and angiotensin converting enzyme 2 in the heart. 1980 91


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