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)

Angiotensin II type 1 (AT(1)) receptor signaling has been implicated in cerebral microvascular alterations associated with ischemia, diabetes mellitus, hypercholesterolemia, and atherosclerosis. Platelets, which express AT(1) receptors, also appear to contribute to the thrombogenic and inflammatory responses that are elicited by these pathological conditions. This study assesses the role of AT(1) receptor activation on platelet-leukocyte-endothelial cell interactions elicited in cerebral microvasculature by ischemia and reperfusion. Intravital microscopy was used to monitor the adhesion of platelets and leukocytes that were labeled with different fluorochromes, whereas dihydrorhodamine-123 was used to quantify oxygen radical production in cerebral surface of mice that were either treated with the AT(1) receptor agonist Val-angiotensin II (ANG II) or subjected to bilateral common carotid artery occlusion (BCCAO) followed by reperfusion. ANG II elicited a dose- and time- dependent increase in platelet-leukocyte-endothelial cell interactions in cerebral venules that included rolling platelets, adherent platelets on the leukocytes and the endothelial cells, rolling leukocytes, and adherent leukocytes. All of these interactions were attenuated by treatment with either P-selectin or P-selectin glycoprotein ligand 1 (PSGL-1) antibody. The AT(1) receptor antagonist candesartan and losartan as well as diphenyleneiodonium, an inhibitor of flavoproteins including NAD(P)H oxidase, significantly reduced the platelet-leukocyte-endothelial cell interactions elicited by either ANG II administration or BCCAO/reperfusion. The increased oxygen radical generation elicited by BCCAO/reperfusion was also attenuated by candesartan. These findings are consistent with an AT(1) receptor signaling mechanism, which involves oxygen radical production and ultimately results in P-selectin- and PSGL-1-mediated platelet-leukocyte-endothelial cell interactions in the cerebral microcirculation.
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PMID:Angiotensin II type 1 receptor signaling contributes to platelet-leukocyte-endothelial cell interactions in the cerebral microvasculature. 1722 Jan 90

Angiotensin II exerts its central nervous system effects primarily via its receptors AT1 and AT2, and it participates in the pathogenesis of ischemia via AT1. The selective AT1 receptor blocker (ARB) is used in the hypertension treatment, and it exerts a variety of pleiotropic effects, including antioxidative, antiapoptotic, and anti-inflammatory effects. In this study, we investigated the therapeutic effect of the ARB telmisartan in experimental intracerebral hemorrhage (ICH) in normotensive rats. ICH was induced via the collagenase infusion or autologous blood injection. Either telmisartan at 30 mg/kg/dose or phosphate-buffered saline was orally administered 2 h after ICH induction. We evaluated hemorrhage volume, brain water content, and functional recovery, and we performed the histological analysis for terminal deoxynucleotidyl transferase dUTP nick-end labeling, leukocyte infiltration, and microglia activation. A variety of intracellular signals, in terms of oxidative stress, apoptotic molecules, and inflammatory mediators, were also measured. Telmisartan reduced hemorrhage volume, brain edema, and inflammatory or apoptotic cells in the perihematomal area. Telmisartan was noted to induce the expression of endothelial nitric-oxide synthase and peroxisome proliferator-activated receptor gamma and decrease oxidative stress, apoptotic signal, tumor necrosis factor-alpha, and cyclooxygenase-2 expression. The telmisartan-treated rats exhibited less pronounced neurological deficits and recovered better. Thus, telmisartan seems to offer neural protection, including antiapoptosis, anti-inflammatory, and antioxidant benefits in the intracerebral hemorrhage rat model.
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PMID:Blockade of AT1 receptor reduces apoptosis, inflammation, and oxidative stress in normotensive rats with intracerebral hemorrhage. 1753 8

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

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

Reactive oxygen species are known to be derived from NADPH oxidase in several tissues. Angiotensin II was suggested to be involved in the activation of NADPH oxidase; however, its role in the gastric mucosa is unclear. We examined the roles of angiotensin II receptor and NADPH oxidase in ischemia/reperfusion-induced gastric damage in rats. Under urethane anesthesia, male Sprague-Dawley rat stomachs were mounted in an ex-vivo chamber, had 100 mM HCl applied to them, and then a catheter was passed through the femoral vein. Ischemia/reperfusion was accompanied by blood collection and reperfusion through the catheter. Losartan, candesartan, valsartan, which are AT1 receptor blockers (ARB); PD123319, an AT2 receptor blocker; enalapril, an ACE inhibitor; or diphenylene iodonium, a NADPH oxidase inhibitor, was given i.v. 10 mins, and beta-NADPH, a NADPH oxidase substrate, was given i.v. 5 mins before reperfusion. The gastric damage by ischemia/reperfusion was attenuated by treatment with any of ARB or enalapril, but was not affected by PD123319. The increase in gastric H(2)O(2) production and microvascular permeability by ischemia/reperfusion was also suppressed by treatment with any of ARB or enalapril. In rat gastric mucosa, the NADPH oxidase subunit p47(phox) was detected. Additionally, diphenylene iodonium had similar effects to ARB against ischemia/reperfusion-caused gastric damage, increased H(2)O(2) production, and microvascular permeability. Ischemia/reperfusion activated NADPH oxidase in the gastric mucosa, and the activation was significantly attenuated by treatment with losartan or diphenylene iodonium. These results suggest that ischemia/reperfusion generated reactive oxygen species are derived from NADPH oxidase activation via AT1 receptor in rat stomachs.
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PMID:Evidence for the involvement of NADPH oxidase in ischemia/reperfusion-induced gastric damage via angiotensin II. 2043 17

Poor adaptation to stress, alterations in cerebrovascular function and excessive brain inflammation play critical roles in the pathophysiology of many psychiatric and neurological disorders such as major depression, schizophrenia, post traumatic stress disorder, Parkinson's and Alzheimer's diseases and traumatic brain injury. Treatment for these highly prevalent and devastating conditions is at present very limited and many times inefficient, and the search for novel therapeutic options is of major importance. Recently, attention has been focused on the role of a brain regulatory peptide, Angiotensin II, and in the translational value of the blockade of its physiological AT(1) receptors. In addition to its well-known cardiovascular effects, Angiotensin II, through AT(1) receptor stimulation, is a pleiotropic brain modulatory factor involved in the control of the reaction to stress, in the regulation of cerebrovascular flow and the response to inflammation. Excessive brain AT(1) receptor activity is associated with exaggerated sympathetic and hormonal response to stress, vulnerability to cerebrovascular ischemia and brain inflammation, processes leading to neuronal injury. In animal models, inhibition of brain AT(1) receptor activity with systemically administered Angiotensin II receptor blockers is neuroprotective; it reduces exaggerated stress responses and anxiety, prevents stress-induced gastric ulcerations, decreases vulnerability to ischemia and stroke, reverses chronic cerebrovascular inflammation, and reduces acute inflammatory responses produced by bacterial endotoxin. These effects protect neurons from injury and contribute to increase the lifespan. Angiotensin II receptor blockers are compounds with a good margin of safety widely used in the treatment of hypertension and their anti-inflammatory and vascular protective effects contribute to reduce renal and cardiovascular failure. Inhibition of brain AT(1) receptors in humans is also neuroprotective, reducing the incidence of stroke, improving cognition and decreasing the progression of Alzheimer's disease. Blockade of AT(1) receptors offers a novel and safe therapeutic approach for the treatment of illnesses of increasing prevalence and socioeconomic impact, such as mood disorders and neurodegenerative diseases of the brain.
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PMID:Blockade of brain angiotensin II AT1 receptors ameliorates stress, anxiety, brain inflammation and ischemia: Therapeutic implications. 2103 50

Experimental and clinical studies have revealed that angiotensin II type 1 receptor blocker has protective effects against ischemic brain injury, but the mechanism is still obscure. Angiotensin II type 1 receptor blocker may also have effects on neurogenesis through the activation of unblocked angiotensin II type 2 receptors. In this study, we showed that valsartan significantly suppressed superoxide production and cytochrome C release into the cytosol after transient forebrain ischemia and consequently attenuated ischemic neuronal damage without affecting the blood pressure in rats. However, valsartan has none of the expected effects on neurogenesis after ischemia. These results suggest that valsartan has neuroprotective effects on ischemic injury through the suppression of oxidative stress and mitochondrial injury.
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PMID:Effects of valsartan on neuroprotection and neurogenesis after ischemia. 2149 60

Excessive allostatic load as a consequence of deregulated brain inflammation participates in the development and progression of multiple brain diseases, including but not limited to mood and neurodegenerative disorders. Inhibition of the peripheral and brain Renin-Angiotensin System by systemic administration of Angiotensin II AT(1) receptor blockers (ARBs) ameliorates inflammatory stress associated with hypertension, cold-restraint, and bacterial endotoxin administration. The mechanisms involved include: (a) decreased inflammatory factor production in peripheral organs and their release to the circulation; (b) reduced progression of peripherally induced inflammatory cascades in the cerebral vasculature and brain parenchyma; and (c) direct anti-inflammatory effects in cerebrovascular endothelial cells, microglia, and neurons. In addition, ARBs reduce bacterial endotoxin-induced anxiety and depression. Further pre-clinical experiments reveal that ARBs reduce brain inflammation, protect cognition in rodent models of Alzheimer's disease, and diminish brain inflammation associated with genetic hypertension, ischemia, and stroke. The anti-inflammatory effects of ARBs have also been reported in circulating human monocytes. Clinical studies demonstrate that ARBs improve mood, significantly reduce cognitive decline after stroke, and ameliorate the progression of Alzheimer's disease. ARBs are well-tolerated and extensively used to treat cardiovascular and metabolic disorders such as hypertension and diabetes, where inflammation is an integral pathogenic mechanism. We propose that including ARBs in a novel integrated approach for the treatment of brain disorders such as depression and Alzheimer's disease may be of immediate translational relevance.
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PMID:Angiotensin II AT(1) receptor blockers ameliorate inflammatory stress: a beneficial effect for the treatment of brain disorders. 2193 88

Angiotensin II (Ang II) is an important regulator of cardiac function and injury in hypertension. The novel Ang IV peptide/AT4 receptor system has been implicated in several physiological functions and has some effects opposite to those of Ang II. However, little is known about the role of this system in Ang II-induced cardiac injury. Here we studied the effect of Ang IV on Ang II-induced cardiac dysfunction and injury using isolated rat hearts, neonatal cardiomyocytes and cardiac fibroblasts. We found that Ang IV significantly improved Ang II-induced cardiac dysfunction and injury in the isolated heart in response to ischemia/reperfusion (I/R). Moreover, Ang IV inhibited Ang II-induced cardiac cell apoptosis, cardiomyocyte hypertrophy, and proliferation and collagen synthesis of cardiac fibroblasts; these effects were mediated through the AT4 receptor as confirmed by siRNA knockdown. These findings suggest that Ang IV may have a protective effect on Ang II-induced cardiac injury and dysfunction and may be a novel therapeutic target for hypertensive heart disease.
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PMID:Angiotensin IV protects against angiotensin II-induced cardiac injury via AT4 receptor. 2196 9


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