While blockade of the renin angiotensin system (RAS) is beneficial in treating many patients with diabetic nephropathy, some patients show a poor response. We hypothesized that the poor response of RAS blockade is attributed to inability to stimulate endothelial nitric oxide. Recently, we reported that diabetic eNOS knockout (KO) mice develop advanced diabetic nephropathy similar to human disease. Here, we tested the hypothesis that blockade of the RAS would be less beneficial in this model than in diabetic wild-type mice. Both enalapril and telmisartan were less effective at reducing renal injury in diabetic eNOSKO mice compared with diabetic wild-type mice. Blood pressure was only transiently reduced by these treatments in diabetic eNOSKO mice and later returned to levels similar to that of untreated diabetic eNOSKO mice. Serum aldosterone tended to be paradoxically higher with enalapril or telmisartan in diabetic eNOSKO mice, whereas these treatments tended to lower aldosterone in diabetic wild-type mice. The pathogenic role of aldosterone was demonstrated by the evidence that spironolactone significantly reduced blood pressure and prevented renal injury. In addition, a higher dose of enalapril also failed to prevent hypertension and renal injury in diabetic eNOSKO mice. In conclusion, an impaired endothelial NO response could lessen the benefit of RAS inhibition in diabetic renal disease. Aldosterone blockade may provide superior protection in this setting. less...

INTRODUCTION: Circulating endothelial progenitor cells (EPCs) provide an endogenous repair mechanism of the dysfunctional endothelium and therefore can play a crucial role in the pathophysiology of coronary artery disease (CAD). Angiotensin II receptor antagonism has been shown to be able to increase EPCs in hypertension but its effect in patients with CAD is unknown. Aim of this study was to evaluate whether telmisartan, an angiotensin II receptor antagonist, can modify the number of subpopulations of EPCs and may in turn affect the endothelial function of normotensive patients with CAD. METHODS: In a prospective double-blind parallel group study, 40 normotensive patients with CAD were randomly treated with telmisartan (80mg) or placebo for 4 weeks at time of coronary angiography. Measurements of EPCs and assessment of flow-mediated dilatation (FMD) of the brachial artery was performed before and after therapy. RESULTS: Absolute number of EPCs was similar at baseline in the telmisartan and placebo groups. After 4 weeks treatment, CD34+/KDR+/CD45- cells increased significantly in the telmisartan group (from 0.010+/-0.003 to 0.014+/-0.004%, P=0.0001) but not in the placebo group (from 0.009+/-0.004 to 0.009+/-0.005%, NS). Similarly, CD133+/KDR+/CD45- cells raised significantly with telmisartan (from 0.003+/-0.002 to 0.006+/-0.002%, P=0.0001) but not with placebo (from 0.004+/-0.003 to 0.003+/-0.002%, NS). Also, CD14+/CD45+ cells increased significantly with telmisartan (from 0.005+/-0.002 to 0.008+/-0.002%, P=0.0001) and were unchanged with placebo (0.006+/-0.002 vs. 0.005+/-0.003%, NS). FMD improved significantly in patients who received telmisartan (10.4+/-3.9%, P=0.0015 vs. baseline) but did not change in the placebo group (5.9+/-2.8%; P=0.32 vs. baseline; telmisartan vs. placebo, P=0.002). A significant positive correlation was found in the telmisartan group between the improvement in FMD and the increase in CD34+/KDR+/CD45- cells and CD133+/KDR+/CD45- cells (r=0.55, P<0.01, and r=0.49, P<0.05, respectively). CONCLUSION: Angiotensin II receptor antagonism with telmisartan increases the number of regenerative EPCs and improves endothelial function in normotensive patients with CAD. These novel effects are interrelated and can explain, at least in part, why telmisartan has beneficial cardiovascular effects independent of its blood pressure lowering action. less...

OBJECTIVES: The aim of the study was to examine the effect of the antihypertensive AT1 receptors antagonist telmisartan on cardiovascular autonomic function and QT dispersion in hypertensive patients with LVH. METHODS: Twenty-five patients (18 males and seven women, mean age 49.8+/-5.2 years) with mild essential arterial hypertension and LVH were compared with 25 age-matched healthy controls. All the participants underwent a complete clinical examination, including electrocardiogram for QT interval measurements and 24h ambulatory ECG monitoring for measurement of heart rate variability. The ECG, 24h ambulatory ECG, and echocardiogram were repeated after eight weeks of treatment. RESULTS: At baseline, hypertensive patients showed QT dispersion (p<0.001) and QTc dispersion (p<0.001) significantly higher than control subjects. An eight-week telmisartan treatment significantly reduced blood pressure (p<0.0001), without significant change in left ventricular mass. Telmisartan-based treatment induced an increased vagal activity without significant change of sympathetic activity and a reduction of QT dispersion (p<0.001) and QTc dispersion (p<0.001). CONCLUSIONS: These data suggest that therapy with telmisartan significantly improves the sympathovagal balance increasing parasympathetic activity, and cardiac electrical stability reducing the heterogeneity of ventricular repolarization in hypertensive subjects. These effects could contribute to reduce arrhythmias as well as sudden cardiac death in at-risk hypertensive patients. less...

BACKGROUND: Chronic rejection remains the most prominent cause of graft failure after transplantation. Recently, it was reported that telmisartan can function as a partial agonist of peroxisome proliferator-activated receptor gamma (PPARgamma) in addition to a blocker of angiotensin II receptor. We investigated the effect of telmisartan on chronic rejection. METHODS: Hearts from Bm12 mice were transplanted into C57BL/6 mice (Class II mismatch), and allografts were harvested at 8 weeks after transplantation. Recipient mice were fed either control chow or chow containing telmisartan (10 mg/kg/day) from 1 day before transplantation. Proliferation assays of smooth muscle cells (SMCs), which were isolated from the aorta of B/6 mice, was performed. RESULTS: Although severe neo-intimal hyperplasia developed in allografts from control mice fed chow (luminal occlusion 70.9 +/- 6.1%), neo-intimal hyperplasia was significantly attenuated in allografts from mice fed chow containing telmisartan (30.0 +/- 10%, p < 0.001). Expression of interferon (IFN)-gamma and interleukin (IL)-15 mRNAs and matrix metalloproteinase (MMP)-2 in allografts was significantly lower in telmisartan-treated mice than in control mice. Proliferation of smooth muscle cells (SMCs) in response to fetal bovine serum was suppressed significantly by telmisartan (10 mumol/liter). The PPARgamma antagonist blocked telmisartan-induced suppression of SMC proliferation. CONCLUSIONS: Telmisartan attenuates SMC proliferation via PPARgamma activity and suppresses neo-intimal hyperplasia after transplantation. Telmisartan may be useful for suppressing chronic allograft rejection. less...

BACKGROUND: Insulin resistance (IR) is common among patients on dialysis and is worse among patients on peritoneal dialysis (PD) than among patients on hemodialysis In this study we tested the hypothesis that administration of telmisartan, an angiotensin II type 1 receptor antagonist, might improve insulin sensitivity in patients on PD. Method: This was a crossover study of 30 nondiabetic patients with end-stage renal disease being treated with PD. Group A patients (n = 15) received telmisartan and other antihypertensive drugs for 4 months, followed by 4 months without telmisartan. Group B patients (n = 15) received their usual treatment for 4 months, followed by 4 months of treatment with telmisartan. Blood glucose and serum insulin levels were monitored and homeostasis model assessment method for IR (HOMA-IR) was calculated. RESULTS: Treatment with telmisartan had no significant impact on serum glucose, potassium, and bicarbonate levels. However, telmisartan significantly reduced serum insulin levels and the HOMA index in groups A and B. CONCLUSION: This study demonstrated that telmisartan, an angiotensin receptor type 1 antagonist, may effectively improve insulin sensitivity as measured by HOMA in patients treated with PD. less...

Introduction For a small number of drugs circadian variability has been shown to modify efficacy, safety, or pharmacokinetics. Objective of the study We aimed to develop a database containing optimum timing of drug administration and to test how well such information is considered in daily practice. Setting University hospital providing primary and tertiary care. Methods We included data of randomised controlled trials collected from Embase and Medline studying the impact of the timing of drug administration on pharmacodynamics, pharmacokinetics, and adverse events. Data were analysed and weighed according to an algorithm considering trial design and assessed endpoints. Each branch of the algorithm led to a specific recommendation as to the time of the day the drug should be administered. A second algorithm was used to establish a recommendation if studies differed in their conclusion. Subsequently we retrospectively analysed the dosing time in consecutive electronic prescriptions issued at our institution in 2007. Results For 30 active compounds randomised controlled trials were published assessing optimum timing of their administration. In 33% of them timing had no impact on clinical endpoints while the administration at a certain time of the day significantly improved the outcome of another 64% no clear statement was made for one drug (ketoprofen). We then analysed 478864 electronic prescriptions. Two percent of them contained drugs with known circadian variability. Only in 14% the suggested time was considered with a range between 0% for telmisartan (bedtime administration) and 85% for perindopril (morning administration). Conclusion Thus far, dedicated studies on circadian responsiveness to drugs are sparse and for the few drugs with unequivocal evidence this information is only rarely considered in daily practice. Integration of circadian dosing information into a clinical decision support system linked to electronic prescribing may be one promising way to make this information widely accessible. less...

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. less...

In addition to lowering blood pressure, telmisartan, an angiotensin (AT(1)) receptor blocker, has recently been shown to exert pleiotropic effects as a partial agonist of nuclear peroxisome proliferator-activated receptor gamma (PPARgamma). On the basis of these findings and docking pose similarity between telmisartan and rosiglitazone in PPARgamma active site, two classes of benzimidazole derivatives were designed and synthesized as dual PPARgamma agonist/angiotensin II antagonists for the possible treatment of metabolic syndrome. Compound 4, a bisbenzimidazole derivative showed the best affinity for the AT(1) receptor with a K(i) = 13.4 nM, but it was devoid of PPARgamma activity. On the other hand 9, a monobenzimidazole derivative, showed the highest activity in PPARgamma transactivation assay (69% activation) with no affinity for the AT(1) receptor. Docking studies lead to the designing of a molecule with dual activity, 10, with moderate PPARgamma activity (29%) and affinity for the AT(1) receptor (K(i) = 2.5 muM). less...

Starting from the structure of Telmisartan, a new series of potent and selective PPARgamma modulators was identified. The synthesis, in vitro and in vivo evaluation of the most potent compounds are reported and the X-ray structure of compound 7b bound to the PPARgamma ligand binding domain is described. less...

OBJECTIVE: To evaluate the literature examining the efficacy of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) for migraine prophylaxis. DATA SOURCES: MEDLINE (1966-October 2009) and International Pharmaceutical Abstracts were searched using the terms migraine, headache, renin-angiotensin system, angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, aldosterone antagonist, and the individual agents in these classes. STUDY SELECTION AND DATA EXTRACTION: English-language human clinical trials, case reports, and systematic reviews were evaluated for efficacy and safety data. The references of reviewed articles were examined to identify additional sources. DATA SYNTHESIS: Preventative trials evaluating ACE inhibitors consist of a case series, 2 open-label trials, and a placebo-controlled trial. Lisinopril reduced headache hours 20%, headache days 17%, and migraine days 21% versus placebo in the controlled trial (p < 0.05). Clinically significant (>50%) reductions in migraine measures were more common (52-66%) in open-label ACE inhibitor trials than in the controlled (32-36%) trial. Preventive trials evaluating ARBs consist of a meta-analysis, an open-label trial, and 2 placebo-controlled trials. Candesartan reduced headache hours 31%, headache days 26%, and migraine days 28% versus placebo in the first controlled trial (p </= 0.001). Telmisartan did not reduce any prespecified primary or secondary outcome measures in the second controlled trial. Clinically significant reductions (>50%) in migraine measures were more common (54-88%) in open-label ARB trials than in the controlled (26-38%) trials. A prescription database review found that ACE inhibitor or ARB therapy halved the use of abortive migraine agents compared to diuretic therapy. CONCLUSIONS: ACE inhibitors and ARBs have migraine prophylaxis activity similar to that of some currently utilized agents. Low-dose lisinopril or candesartan may be reasonable second- or third-line agents, particularly in patients with other indications for ACE inhibitor or ARB therapy. Further controlled clinical trials are needed to delineate the role of these agents in migraine prevention. less...