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:C0020538 (hypertension)
170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the ability of angiotensin II type 1 (AT1) receptor blockers with peroxisome proliferator-activated receptor (PPAR)-gamma agonist activity (telmisartan and irbesartan) and AT1 receptor blockers devoid of PPARgamma agonist activity (eprosartan and valsartan) to inhibit vascular cell proliferation studied in the absence of angiotensin II stimulation. Telmisartan and, to a lesser extent, irbesartan inhibited proliferation of human aortic vascular smooth muscle cells in a dose-dependent fashion, whereas eprosartan and valsartan did not. To investigate the role of PPARgamma in the antiproliferative effects of telmisartan, we studied genetically engineered NIH3T3 cells that express PPARgamma. Pioglitazone inhibited proliferation of NIH3T3 cells expressing PPARgamma but had little effect on control NIH3T3 cells that lack PPARgamma. In contrast, telmisartan inhibited proliferation equally in NIH3T3 with and without PPARgamma. Valsartan failed to inhibit proliferation of either cell line. In addition, telmisartan inhibited proliferation equally in aortic smooth muscle cells derived from mice with targeted knockout of PPARgamma in the smooth muscle and from control mice, whereas valsartan had no effect on cell proliferation. Telmisartan, but not valsartan, reduced phosphorylation of AKT but not extracellular signal-regulated kinase otherwise induced by exposure to serum of quiescent human smooth muscle cells, quiescent mice smooth muscle cells lacking PPARgamma, or quiescent Chinese hamster ovary-K1 cells lacking the AT1 receptor. In summary, the antiproliferative effects of telmisartan in the absence of exogenously supplemented angiotensin II involve more than just AT1 receptor blockade and do not require activation of PPARgamma. It might be postulated that inhibition of AKT activation is a mechanism mediating the antiproliferative effects of telmisartan, including in cells lacking AT1 receptors or PPARgamma.
Hypertension 2009 Dec
PMID:Telmisartan-induced inhibition of vascular cell proliferation beyond angiotensin receptor blockade and peroxisome proliferator-activated receptor-gamma activation. 1982 96

Hypertension is a comorbidity of Type 2 diabetes, and blood pressure lowering has been shown to reduce cardiovascular (CV) and renal disease progression in this population. Angiotensin-converting enzyme (ACE)-inhibitors have demonstrated reduction in CV mortality and myocardial infarction, stroke, and heart failure in patients with diabetes. Evidence suggests that angiotensin receptor blockers (ARBs) have similar CV protective effects, particularly in patients post-myocardial infarction and in those with heart failure, and their renoprotective effects have reduced proteinuria in patients with or without diabetes. In addition, ARBs have been shown to reduce diabetic nephropathy and complications related to nephropathy. The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint trial (ONTARGET) is the first trial to demonstrate that the ARB, telmisartan, is as effective as the ACE-inhibitor, ramipril, in CV protection in a high-risk, ACE-tolerant population. Whether all ARBs are equally cardioprotective is uncertain. Data indicate that the beneficial effects of telmisartan may be drug specific rather than constitute a 'class effect.'
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PMID:Role of angiotensin receptor blockers in diabetes: implications of recent clinical trials. 1990 19

Hypertensive vascular disorders are characterized by endothelial dysfunction. Loss of renal autoregulation causes glomerular hypertension. However, the relationship between the autoregulatory response and glomerular damage has not been well examined. We examined the contributions of uncoupled endothelial nitric oxide synthase (eNOS) in hypertensive renal disease, and the relationship between the degree of autoregulation impairment and glomerular injury. We also investigated the effects of telmisartan on eNOS coupling and renal autoregulation. Male Dahl salt-sensitive hypertensive (DS) rats (14-week old) fed an 8% salt diet were used to examine endothelial dysfunction and impaired renal autoregulation caused by glomerular hypertension. Some DS rats were treated with telmisartan (3.0 mg kg(-1) day(-1)), an angiotensin receptor blocker, for 2 weeks. Increased superoxide production and decreased nitric oxide production, as detected by fluorescent indicator perfusion methods, were observed in the glomeruli and arterioles of hypertensive DS rats. Telmisartan improved the imbalance of superoxide and nitric oxide in the glomeruli and arterioles. Decreased serum tetrahydrobiopterin levels and coupled eNOS seen in the DS rat kidney were improved with telmisartan treatment. The endothelial relaxation reaction was impaired in DS rat aortic arteries. Autoregulatory capacity in response to step changes in perfusion pressure was also impaired in DS rat kidney. Treatment with telmisartan improved these abnormalities. Endothelial dysfunction in the glomeruli and impaired renal autoregulation, which may cause glomerular sclerosis, were observed in DS rat kidney. Telmisartan treatment improves these dysfunctions in hypertensive renal disease.
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PMID:Telmisartan improves endothelial dysfunction and renal autoregulation in Dahl salt-sensitive rats. 2005 87

The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) showed that the angiotensin receptor blocker telmisartan 80 mg was not inferior to the angiotensin-converting enzyme inhibitor ramipril 10 mg, and the combination no more effective than ramipril alone, in decreasing morbidity and mortality in patients with cardiovascular disease or high-risk diabetes. Although therapy targeting angiotensin II is known to decrease left ventricular (LV) mass and volume, the relative influence of angiotensin-converting enzyme inhibitor inhibitors and angiotensin receptor blocker, and their combination, on the heart remains unclear in this population. Magnetic resonance imaging was performed in 287 patients enrolled in ONTARGET, across 8 centers in 6 countries, at randomization and after 2-year treatment (90, 100, and 97 patients in the ramipril, telmisartan, and combination therapy groups, respectively). Baseline patient characteristics showed higher frequencies of coronary artery disease, Asian ethnicity, and use of statins and beta blockers than the main ONTARGET trial. LV mass decreased in all groups (p <0.0001 for each), but there were no significant differences in change in LV mass or volume among groups, except that LV mass index decreased more on combination versus telmisartan (p = 0.04). Key determinants of LV mass decrease were a history of hypertension (p = 0.03), baseline mass (p <0.0001), and decrease in systolic blood pressure (p <0.0001). The best magnetic resonance imaging predictor of composite events was end-systolic volume (p <0.0001). In conclusion, telmisartan and ramipril had similar effects on LV mass and volume, and combination therapy was not more effective, in high-risk patients with cardiovascular disease. These results are consistent with the major outcome findings of the main ONTARGET study.
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PMID:Left ventricular mass and volume with telmisartan, ramipril, or combination in patients with previous atherosclerotic events or with diabetes mellitus (from the ONgoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial [ONTARGET]). 1993 79

Angiotensin-receptor blockers (ARBs) offer superior tolerability to angiotensin-converting enzyme inhibitors, and are increasingly used in patient management. ARBs vary in their pharmacological profiles, which results in efficacy differences. Therefore, deciding between ARBs should be evidence-based and related to the specific requirements of the individual patient. For patients with hypertension but at low additional risk, an ARB that provides sustained, powerful 24-h reductions in blood pressure is suitable. For patients at very high additional risk (with heart failure), an ARB with demonstrated efficacy in this patient population is the preferred option. For patients at increased risk, telmisartan should be the ARB of choice based on the results from the Ongoing Telmisartan Alone and in Combination with Ramipril Global End Point Trial (ONTARGET), which demonstrated for the first time that an ARB has equivalent protection to the reference angiotensin-converting enzyme inhibitor in a broad cross-section of at-risk patients but a better side-effect profile.
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PMID:Choosing an angiotensin-receptor blocker: blood pressure lowering, cardiovascular protection or both? 2001 92

The primary aim of the treatment in hypertension is to prevent cardiovascular complications. All hypertensives reduce the risk for cardiovascular events by providing effective blood pressure control. Besides blood pressure-lowering effect, the contribution of an antihypertensive agent to reduce the risk for cardiovascular events at high-risk patients was first demonstrated in 2000 in the HOPE study (Heart Outcomes Prevention Evaluation), which used an angiotensin-converting enzyme (ACE) inhibitor, ramipril 10 mg (N Engl J Med 2000;342:145-53). However, at the time the results of this study appeared, the use of angiotensin-receptor blockers (ARB) was gaining popularity in the treatment of hypertension as an alternative to ACE inhibitors. This raised the question as to whether an ARB would also offer benefit comparable to that derived from ramipril. A non-inferiority trial was planned by the same research group to test whether telmisartan 80 mg was as effective as ramipril 10 mg in a similar patient population. In order to obtain reliable results, 25,000 patients from all over the world had to be followed-up for five years (Am Heart J 2004;148:52-61). The results of the ONTARGET study (The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial) which were presented at the annual meeting of the American College of Cardiology in March 2008 were suggestive of a new indication for telmisartan. In August, 2009, the U.S. Food and Drug Administration reported that a new indication might be justified for the use of telmisartan, an angiotensin-receptor blocker: In order to reduce the risk for cardiovascular diseases and if an ACE inhibitor (ramipril 10 mg) cannot be used, telmisartan 80 mg can be used in patients with a high cardiovascular risk profile (Press announcements, FDA). The aim of this review is to provide a comprehensive analysis of the course of this recent development in cardiovascular protection.
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PMID:[Renin-angiotensin-aldosterone system inhibition and cardiovascular protection]. 2001 67

The importance of hypertension treatment has expanded beyond blood pressure management to include additional risk factors, mainly diabetes. It was considered of interest to test the effect of telmisartan, an angiotensin receptor 1 antagonist and peroxisome proliferator activator receptor-gamma partial agonist, on Cohen-Rosenthal diabetic hypertensive nonobese (CRDH) rats, a unique model combining both pathologies. Its effect was examined on fat-derived and inflammatory agents in CRDH. To determine the extent of the drug's peroxisome proliferator activator receptor-gamma modulating beneficial metabolic actions, results were compared with those obtained with valsartan and rosiglitazone in CRDH and Cohen diabetic rat (CDR). Telmisartan and valsartan were given in drinking water at 3 and 12 mg/kg/d, whereas rosiglitazone (3 mg/kg/d) was given as food admixture for a period of 5 months. Blood pressure, glucose, insulin, adiponectin, leptin, and tumor necrosis factor alpha were examined. Telmisartan and valsartan significantly (P < .01) reduced blood pressure, whereas telmisartan and rosiglitazone considerably reduced blood glucose levels to normoglycemic levels (P < .01) in these 2 strains. Insulin levels were not affected by telmisartan and valsartan but were slightly reduced by rosiglitazone in CDR. In contrast to valsartan, adiponectin was significantly (60%, P < .01) increased by telmisartan in both CDR and CRDH, whereas rosiglitazone induced a 60% and 180% increase in CRDH and CDR animals, respectively, on day 30 of treatment. Co-treatment with GW9662 averted telmisartan-induced rise of adiponectin. Tumor necrosis factor alpha declined in telmisartan-treated rats, less so with rosiglitazone, but not valsartan. Telmisartan also induced downsizing of epididymal adipocytes compared with valsartan. Leptin levels were significantly increased by valsartan (P < .05) but reduced by telmisartan and rosiglitazone. The telmisartan-induced increase in adiponectin was most probably associated with a decrease in glucose and tumor necrosis factor alpha levels. Therefore, in addition to its hypotensive effect, telmisartan demonstrated beneficial thiazolidinedione-like effects.
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PMID:Telmisartan ameliorates hyperglycemia and metabolic profile in nonobese Cohen-Rosenthal diabetic hypertensive rats via peroxisome proliferator activator receptor-gamma activation. 2007 Sep 92

The renin-angiotensin-aldosterone system (RAAS) plays an important role in the pathogenesis of a variety of clinical conditions, including atherosclerosis, hypertension, left ventricular hypertrophy, myocardial infarction, and heart failure. Inhibition of the RAAS with either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ARBs) has been shown to be effective in lowering blood pressure and reducing cardiovascular mortality and morbidity in various at-risk patient populations. A number of studies have shown that these 2 classes are effective in reducing the rate of renal disease progression in patients with diabetic nephropathy, although more long-term vascular outcome studies are needed in patients with chronic kidney disease. The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) was the first study to show comparable reno- and cardioprotective effects between an ARB (telmisartan) and ramipril in a broad section of at-risk patients, on top of usual standard care. However, telmisartan showed better tolerability than ramipril in ONTARGET, with less cough and angioedema. This difference was obtained despite patients having been selected for tolerability to both drugs at study entry.
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PMID:Renin-angiotensin system blockade and cardiovascular and renal protection. 2045 6

Telmisartan shows antihypertensive and several pleiotropic effects that interact with metabolic pathways. In the present study we tested the hypothesis that telmisartan prevents adipogenesis in vitro and weight gain in vivo through activation of peroxisome proliferator-activated receptor (PPAR)-delta-dependent pathways in several tissues. In vitro, telmisartan significantly upregulated PPAR-delta expression in 3T3-L1 preadipocytes in a time- and dose-dependent manner. Other than enhancing PPAR-delta expression by 68.2+/-17.3% and PPAR-delta activity by 102.0+/-9.0%, telmisartan also upregulated PPAR-gamma expression, whereas neither candesartan nor losartan affected PPAR-delta expression. In vivo, long-term administration of telmisartan significantly reduced visceral fat and prevented high-fat diet-induced obesity in wild-type mice and hypertensive rats but not in PPAR-delta knockout mice. Administration of telmisartan did not influence food intake in mice. Telmisartan influenced several lipolytic and energy uncoupling related proteins (UCPs) and enhanced phosphorylated protein kinase A and hormone sensitive lipase but reduced perilipin expression and finally inhibited adipogenesis in 3T3-L1 preadipocytes. Telmisartan-associated reduction of adipogenesis in preadipocytes was significantly blocked after PPAR-delta gene knockout. Chronic telmisartan treatment upregulated the expressions of protein kinase A, hormone-sensitive lipase, and uncoupling protein 1 but reduced perilipin expression in adipose tissue and increased uncoupling protein 2 and 3 expression in skeletal muscle in wild-type mice but not in PPAR-delta knockout mice. We conclude that telmisartan prevents adipogenesis and weight gain through activation of PPAR-delta-dependent lipolytic pathways and energy uncoupling in several tissues.
Hypertension 2010 Apr
PMID:Telmisartan prevents weight gain and obesity through activation of peroxisome proliferator-activated receptor-delta-dependent pathways. 2017 98

ATP-binding cassette (ABC)-transporters, such as P-glycoprotein (P-gp/ABCB1), multidrug resistance-associated proteins (MRPs/ABCCs) and breast cancer resistance protein (BCRP/ABCG2) transport numerous drugs thus regulating their absorption, distribution and excretion. Angiotensin receptor type 1 blockers (ARBs), used to treat hypertension and heart failure, are commonly administered in combination therapy. However, their interaction potential is not well studied and their effect on ABC-transporters remains elusive. The study therefore aimed to elucidate the effect of various ARBs (telmisartan, candesartan, candesartan-cilexetil, irbesartan, losartan, olmesartan, olmesartan-medoxomil, eprosartan) on ABC-transporter activity in vitro. P-gp inhibition was assessed by calcein assay, BCRP inhibition by pheophorbide A efflux assay, and MRP2 inhibition by a MRP2 PREDIVEZ Kit. Induction of P-gp, BCRP and MRP2 was assessed by real time reverse transcriptase polymerase chain reaction and for P-gp also in a functional assay. Telmisartan was identified as one of the most potent inhibitors of P-gp currently known (IC(50)=0.38+/-0.2 microM for murine P-gp) and it also inhibited human BCRP (IC(50)=16.9+/-8.1 microM) and human MRP2 (IC(50)=25.4+/-0.6 microM). Moreover, the prodrug candesartan-cilexetil, but not candesartan itself, significantly inhibited P-gp and BCRP activity. None of the compounds tested induced mRNA transcription of P-gp or BCRP but eprosartan and olmesartan induced MRP2 mRNA expression. In conclusion, telmisartan substantially differed from other ARBs with respect to its potential to inhibit ABC-transporters relevant for drug pharmacokinetics and tissue defense. These findings may explain the known interaction of telmisartan with digoxin and suggest that it may modulate the bioavailability of drugs whose absorption is restricted by P-gp and possibly also by BCRP or MRP2.
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PMID:Interaction of angiotensin receptor type 1 blockers with ATP-binding cassette transporters. 2022 53


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