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)

Experimental renal ischaemic injuries are typically produced by temporary closure of the renal artery. In rats, two different methods of such temporary closure of the renal artery were compared: snaring of the artery by tourniquet, and clamping by a microsurgical bulldog clamp. The consequences of ischaemic periods 60, 90 and 120 minutes were evaluated. In different experimental series, the potential protective effect of non-peptic AT1 angiotensin II receptor antagonist losartan on postischaemic renal injury was evaluated. The seven-day survival and the degree of functional renal damage (according to the plasma levels of creatinine and urea) were analyzed 24 hours and 7 days after experimental renal ischaemia. Ischaemia, produced by the tourniquet led to a more significant renal damage than ischaemia caused by clamping of the renal artery by a microclamp (higher 7-day mortality rate, higher postischaemic plasma levels of creatinine and urea). Losartan decreased the consequences of renal ischaemia caused by the tourniquet, but did not change the outcome of renal ischaemia produced by microsurgical bulldog clamps. We found, that not only the duration of ischaemia and pharmacology, but even the surgical technique of producing renal ischaemia are important factors in experimental studies evaluating ischaemic renal damage. These findings provide evidence of the role of angiotensin II in postischaemic renal injury by a renal tourniquet. This particular mechanism is probably not involved, when renal artery is gently temporarily closed by a bulldog microclamp.
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PMID:[Experimental ischemic renal injury--effect of surgical technique and the protective effect of a nonpeptide angiotensin II antagonist (losartan)]. 1107 68

Osteopontin (OPN) is a secreted glycoprotein in both phosphorylated and non-phosphorylated forms. It contains an Arg-Gly-Asp cell-binding sequence and a thrombin-cleavage site. OPN is mainly present in the loop of Henle and distal nephrons in normal kidneys in animals and humans. After renal damage, OPN expression may be significantly up-regulated in all tubule segments and glomeruli. Studies utilizing OPN gene-deficient mice, antisense-treated or anti-OPN-treated animals have demonstrated that OPN promotes accumulation of macrophages, and may play a role in macrophage-mediated renal injury, but that the effect may be mild and short-lived. On the other hand, OPN has some renoprotective actions in renal injury, such as increasing tolerance to acute ischemia, inhibiting inducible nitric oxide synthase and suppressing nitric oxide synthesis, reducing cell peroxide levels and promoting the survival of cells exposed to hypoxia, decreasing cell apoptosis and participating in the regeneration of cells. In addition, OPN is associated with renal stones, but whether it acts as a promoter or inhibitor of stone formation is controversial. It has been demonstrated that OPN receptors include two families: integrin and CD44. The OPN integrin receptors include alpha(v)beta(3), alpha(v)beta(1), alpha(v)beta(5) and alpha(9)beta(1), and alpha(4)beta(1). In normal human kidneys, standard CD44 is expressed most dominantly. Different OPN functions are mediated via distinct receptors. Parathyroid hormone, vitamin D(3), calcium, phosphate and some cytokines increase OPN expression in vitro or in vivo, whereas female sex hormones and angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists decrease OPN expression in some renal damage states.
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PMID:Expression, roles, receptors, and regulation of osteopontin in the kidney. 1170 81

Randomized trials in hypertensive patients with atherosclerotic renal artery stenosis (ARAS) mostly did not reveal any significant difference between antihypertensive treatment and revascularization (by angioplasty or bypass surgery) in their effects on blood pressure or glomerular filtration rate. This unexpected conclusion reflects a fact that in addition to potentially reversible ischemia, some other factors which are not eliminated by technically successful revascularization take part in the decrease of renal function in ARAS, including cholesterol microemboli from atherosclerotic plaques, secondary focal segmental glomerulosclerosis and hypertensive nephroangiosclerosis. Moreover, these changes have been also found in the contralateral kidney without any stenosis. Scintigraphic studies confirmed that the individual kidney function was not related to the presence of ARAS, i.e., the glomerular filtration rate in the stenotic kidney was often equal to, or paradoxically even better than that in the kidney with normal renal artery. This has obviously important consequences for the indication of revascularization which should be based on measurement of the individual kidney function rather than overall renal function. A conservative treatment of ARAS should comprise ACE inhibitors or angiotensin II receptor antagonists, statins and acetylsalicylic acid. The long-term effect of such treatment on the progression of atherosclerotic nephropathy is now being evaluated in randomized trials.
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PMID:[Atherosclerotic nephropathy in renal artery stenosis--from randomized studies to individualized therapy]. 1272 96

The renin-angiotensin system evolved to maintain volume homeostasis and blood pressure and to prevent ischemia during acute volume loss. But in the present age, these mechanisms are redundant, and the clinical significance of angiotensin II results from its pathologic effects, which are mediated by the angiotensin II type 1 (AT(1)) receptor. Activation of AT(1) receptors has been linked to pathologic processes that contribute to atherosclerosis and ischemic events, including oxidative stress, inflammatory processes, low-density lipoprotein cholesterol trafficking, and prothrombotic states. The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) program will compare the efficacy of the angiotensin II receptor blocker (ARB) telmisartan, the angiotensin-converting enzyme (ACE) inhibitor ramipril, and combination therapy with telmisartan plus ramipril for reducing cardiovascular risk. The ARB telmisartan is distinguished by its long duration of action, which compares favorably with some other ARBs and conventional antihypertensives. Ramipril was shown in the Heart Outcomes Prevention Evaluation (HOPE) study to reduce the risk for myocardial infarction (MI) and other cardiovascular events in patients at high risk for cardiovascular events but without heart failure or a low ejection fraction. The ONTARGET program consists of 2 randomized, double-blind, multicenter international trials: a principal trial, ONTARGET, and a parallel trial, Telmisartan Randomized Assessment Study in ACE-I Intolerant Patients with Cardiovascular Disease (TRANSCEND). The treatment arms for the principal ONTARGET study are telmisartan 80 mg, ramipril 10 mg, and combination therapy with telmisartan 80 mg plus ramipril 10 mg; for the parallel study TRANSCEND, the treatment arms are telmisartan 80 mg and placebo. Both trials will assess cardiovascular outcomes in patients at high risk using the same criteria as that of the HOPE study, with a single exception: the TRANSCEND trial will enroll patients who do not tolerate ACE inhibitor treatment. The primary end points in both ONTARGET and TRANSCEND are death caused by cardiovascular disease, acute MI, stroke, and hospitalization because of congestive heart failure. The secondary end points include newly diagnosed heart failure, revascularization, new-onset type 2 diabetes mellitus, nephropathy, cognitive decrease and dementia, and newly diagnosed atrial fibrillation; these will be used for hypothesis generation.
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PMID:The ongoing telmisartan alone and in combination with ramipril global endpoint trial program. 1278 6

We investigated the effect of different ACE inhibitors on tissue injury in isolated rat hearts subjected to 30 minutes of ischemia followed by 120 minutes of reperfusion. Zofenoprilat (1-100 microM), but not enalaprilat or lisinopril, significantly reduced infarct size, as estimated on the basis of triphenyltetrazolium chloride staining. The protection was not reproduced by the angiotensin II receptor antagonist irbesartan, and it was partly abolished by the bradykinin receptor antagonist HOE 140. Zofenoprilat molecule contains a sulfhydryl group, and its administration, as compared with enalaprilat or lisinopril administration, was associated with better preservation of protein thiols at the end of ischemia. We conclude that zofenopril has a specific cardioprotective effect, which might be related either to interference with bradykinin metabolism or to preservation of protein sulfhydryl groups.
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PMID:Cardioprotective effect of zofenopril in perfused rat heart subjected to ischemia and reperfusion. 1471 20

A large volume of experimental data supports the presence of apoptosis in failing hearts. Apoptosis in many types of cells results from exposure to cytotoxic cytokines or damaging agents. Cytotoxic cytokines such as tumor necrosis factor (TNF)-alpha or Fas ligand (FasL) bind to their receptors to activate caspase-8, while damaging agents can cause mitochondrial release of cytochrome c, which can initiate activation of caspase-9. Caspase-8 or -9 can activate a cascade of caspases. The p53 protein is often required for damaging agent-induced apoptosis. An imbalance of proapoptotic factors versus prosurvival factors in the bcl-2 family precedes the activation of caspases. Given these typical changes of apoptosis found in many cell types, the apoptotic pathway in cardiomyocytes is somewhat unconventional since in vivo experimental data reveal that apoptosis does not appear to be controlled by TNF-alpha, FasL, p53 or decrease of bcl-2. In vitro and in vivo studies suggest the importance of mitochondria and activation of caspases in cell death occurring in failing hearts. Oxidants, excessive nitric oxide, angiotensin II and catecholamines have been shown to trigger apoptotic death of cardiomyocytes. Eliminating these inducers reduces apoptosis and reverses the loss of contractile function in many cases, indicating the feasibility of the pharmacological application of antioxidants, nitric oxide synthetase inhibitors, ACE inhibitors, angiotensin II receptor antagonists and adrenergic receptor antagonists. Most inducers of apoptosis initiate a cascade of signaling events, including activation of the p38 mitogen-activated protein kinase. Small molecule inhibitors of p38 have been shown to be capable of preventing apoptosis and loss of contractile function associated with ischemia and reperfusion. Although further experimental work is needed, several studies have already indicated the beneficial effect of caspase inhibitors against cell loss and features of heart failure in vitro and in vivo. These studies indicate the importance of inhibiting apoptosis in therapeutic interventions against heart failure.
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PMID:Apoptosis and heart failure: mechanisms and therapeutic implications. 1472 98

This article summarizes the main mechanisms responsible for the ischemia-induced neovascularization. Growth factors and inflammatory agents are the most powerful actors in the neo-vascularization process. Numerous other factors have been shown to modulate blood vessel growth. Among these, we have tested the potential effect of angiotensin II in several in vivo models of angiogenesis. Angiotensin II has pro-angiogenic effects via its AT1 subtype receptor whereas the AT2 angiotensin II receptor has pro-apoptotic and anti-angiogenic properties. Besides its effect on angiotensin II formation, some angiotensin-converting-enzyme inhibitors have pro-angiogenic effect by increasing the local concentration of bradykinin in ischemic tissues and, thus, by activation of its B2 receptor and then NO release. These besides the "classical" gene and cellular therapies designed for the treatment of pathological tissue ischemia, alternative strategies using new pharmacological properties of drugs acting on the renin angiotensin system are likely to be possible.
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PMID:[The renin-angiotensin system and post-ischemic angiogenesis]. 1558 84

The aim of our study was to investigate the changes in the early stages (at weeks 2 and 4) of experimental acute renal failure after short-time ischemia-reperfusion (I/R) compared with the impact of Losartan. Twenty male Wistar rats were divided into three groups: sham-operated rats (2 weeks), I/R groups (2 and 4 weeks); I/R and Losartan-treated groups (2 and 4 weeks). I/R was produced in adult rats by clamping the left kidney renal artery and renal vein for 40 min. The angiotensin II receptor antagonist Losartan was added to the drinking water (40 mg/l), and treatment was started on the first day after the I/R. Body weight, systolic blood pressure (SBP) and 24 h urine amount was measured every week. Urine amount and SBP was higher in I/R groups compared to sham-operated rats. Early stage acute renal disease was characterized by focal segmental glomerulosclerosis (FSGS) and interstitial fibrosis (IF) at weeks 2 and 4 after I/R. In the Losartan group, 2 weeks after the surgery, FSGS, IF and mesangial cell proliferation was decreased, but at week 4 these parameters showed a tendency to increase. Marked changes take place in tubular epithelial cells, especially in I/R groups. Angiotensin II receptor blocker AT1RA Losartan in the small dose (40 mg/l) had no effect on hypertension and urine excretion in the experimental I/R model. A pilot study revealed that tubular basement membrane thickness is markedly increased after I/R.
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PMID:Morphological changes in experimental postischemic rat kidney. A pilot study. 1583 2

Ischemic diseases are a leading cause of death worldwide. It is becoming increasingly appreciated that atherosclerosis is a major cause of ischemia reperfusion. Hypercholesterolemia is a major risk factor for the development of atherosclerosis, and is associated with an increased incidence of ischemia reperfusion. Furthermore, elevated cholesterol levels exacerbate the vascular responses to ischemia-reperfusion, which intensifies the resulting organ dysfunction. One of the underlying features of both ischemia-reperfusion injury and hypercholesterolemia is the proinflammatory and prothrombogenic phenotype invoked in the microvasculature. This is manifested as an endothelial dysfunction, characterized by leukocyte and platelet recruitment, oxidative stress and angiotensin II receptor Type 1a activation. These common pathways of inflammation offer attractive targets for the development of drugs to combat cardiovascular disease and the associated ischemic disorders.
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PMID:Hypercholesterolemia: its impact on ischemia-reperfusion injury. 1629 97

Assessment of flow-mediated dilation (FMD) after forearm ischemia is widely used as a noninvasive bioassay of stimulated nitric oxide (NO)-mediated conduit artery vasodilator function in vivo. Whether this stimulated endothelial NO function reflects basal endothelial NO function is unknown. To test this hypothesis, retrospective analysis of randomized crossover studies was undertaken in 17 subjects with Type 2 diabetes; 9 subjects undertook an exercise training or control period, whereas the remaining 8 subjects were administered an angiotensin II receptor blocker or placebo. FMD was assessed by using wall tracking of high-resolution brachial artery ultrasound images in response to reactive hyperemia. Resistance vessel basal endothelium-dependent NO function was assessed by using intrabrachial administration of NG-monomethyl-L-arginine (L-NMMA) and plethysmographic assessment of forearm blood flow (FBF). FMD was higher after intervention compared with control/placebo (6.15+/-0.53 vs. 3.81+/-0.72%, P<0.001). There were no significant changes in the FBF responses to L-NMMA. Regression analysis between FMD and L-NMMA responses at entry to the study revealed an insignificant correlation (r=-0.10, P=0.7), and improvements in FMD with the interventions were not associated with changes in the L-NMMA responses (r=-0.04, P=0.9). We conclude that conduit artery-stimulated endothelial NO function (FMD) does not reflect basal resistance vessel endothelial NO function in subjects with Type 2 diabetes.
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PMID:Relationship between changes in brachial artery flow-mediated dilation and basal release of nitric oxide in subjects with Type 2 diabetes. 1656 7


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