Administration Of Telmisartan Research Articles

Pharmacokinetic-pharmacodynamic model of the antihypertensive interaction between telmisartan and hydrochlorothiazide in spontaneously hypertensive rats

The goal of this study was to establish an integrated indirect response pharmacokinetic-pharmacodynamic model between telmisartan and hydrochlorothiazide to describe the antihypertensive interaction of these two drugs in spontaneously hypertensive rats. The blood pressure and plasma concentrations were measured by the tail-cuff test and high performance liquid chromatography-mass spectrometry, respectively, in spontaneously hypertensive rats. The current pharmacokinetic-pharmacodynamic model was based on the non-competitive pharmacodynamic interaction of two drugs acting on different physiological processes. This model was able to acquire the temporal changes in drug concentration and blood pressure after administration of telmisartan or hydrochlorothiazide. The noncompetitive pharmacodynamic interaction assumed that the decreased blood pressure was attributed to the inhibitory function of telmisartan and stimulatory function of hydrochlorothiazide after administration of these two drugs. There was no significant pharmacokinetic change of telmisartan and hydrochlorothiazide in the different groups tested. The model predicted a synergistic pharmacodynamic interaction when telmisartan was administered in combination with hydrochlorothiazide, which was notably stronger than if the effects were additive. The results showed that the presented pharmacokinetic-pharmacodynamic model was suitable for describing the antihypertensive interaction between telmisartan and hydrochlorothiazide.

Telmisartan activates endothelial nitric oxide synthase via Ser1177 phosphorylation in vascular endothelial cells.

Because endothelial nitric oxide synthase (eNOS) has anti-inflammatory and anti-arteriosclerotic functions, it has been recognized as one of the key molecules essential for the homeostatic control of blood vessels other than relaxation of vascular tone. Here, we examined whether telmisartan modulates eNOS function through its pleiotropic effect. Administration of telmisartan to mice significantly increased the phosphorylation level of eNOS (Ser1177) in the aortic endothelium, but administration of valsartan had no effect. Similarly, telmisartan treatment of human umbilical vein endothelial cells significantly increased the phosphorylation levels of AMP-activated protein kinase (Thr172) and eNOS and the concentration of intracellular guanosine 3′,5′-cyclic monophosphate (cGMP). Furthermore, pretreatment with a p38 mitogen-activated protein kinase (p38 MAPK) inhibitor suppressed the increased phosphorylation level of eNOS and intracellular cGMP concentration. These data show that telmisartan increases eNOS activity through Ser1177 phosphorylation in vascular endothelial cells mainly via p38 MAPK signaling.

Partial agonist, telmisartan, maintains PPARγ serine 112 phosphorylation, and does not affect osteoblast differentiation and bone mass.

Peroxisome proliferator activated receptor gamma (PPARγ) controls both glucose metabolism and an allocation of marrow mesenchymal stem cells (MSCs) toward osteoblast and adipocyte lineages. Its activity is determined by interaction with a ligand which directs posttranscriptional modifications of PPARγ protein including dephosphorylation of Ser112 and Ser273, which results in acquiring of pro-adipocytic and insulin-sensitizing activities, respectively. PPARγ full agonist TZD rosiglitazone (ROSI) decreases phosphorylation of both Ser112 and Ser273 and its prolonged use causes bone loss in part due to diversion of MSCs differentiation from osteoblastic toward adipocytic lineage. Telmisartan (TEL), an anti-hypertensive drug from the class of angiotensin receptor blockers, also acts as a partial PPARγ agonist with insulin-sensitizing and a weak pro-adipocytic activity. TEL decreased S273pPPARγ and did not affect S112pPPARγ levels in a model of marrow MSC differentiation, U-33/γ2 cells. In contrast to ROSI, TEL did not affect osteoblast phenotype and actively blocked ROSI-induced anti-osteoblastic activity and dephosphorylation of S112pPPARγ. The effect of TEL on bone was tested side-by-side with ROSI. In contrast to ROSI, TEL administration did not affect bone mass and bone biomechanical properties measured by micro-indentation method and did not induce fat accumulation in bone, and it partially protected from ROSI-induced bone loss. In addition, TEL induced “browning” of epididymal white adipose tissue marked by increased expression of UCP1, FoxC2, Wnt10b and IGFBP2 and increased overall energy expenditure. These studies point to the complexity of mechanisms by which PPARγ acquires anti-osteoblastic and pro-adipocytic activities and suggest an importance of Ser112 phosphorylation status as being a part of the mechanism regulating this process. These studies showed that TEL acts as a full PPARγ agonist for insulin-sensitizing activity and as a partial agonist/partial antagonist for pro-adipocytic and anti-osteoblastic activities. They also suggest a relationship between PPARγ fat “browning” activity and a lack of anti-osteoblastic activity.

Telmisartan Treatment Ameliorates Memory Deficits in Streptozotocin-Induced Diabetic Mice via Attenuating Cerebral Amyloidosis

Telmisartan, an angiotensin II type 1–receptor blocker (ARBs), has been reported to exert beneficial effects on the central nervous system (CNS). However, the effect of telmisartan on cognitive impairment associated with type 1 diabetes is not well known. Here, we examined the possibility that telmisartan could improve memory function in a type 1 diabetic mouse model, streptozotocin (STZ)-induced diabetic mice. STZ-induced diabetic mice subjected to the Morris Water Maze (MWM) task exhibited a significant decline of spatial learning and memory. Oral administration of telmisartan at two nonhypotensive doses (0.7 or 0.35 mg/kg) significantly improved memory deficits in STZ-induced diabetic mice. Telmisartan treatment markedly reduced Aβ42, APP, BACE1, RAGE, and NF-κB p65 of the hippocampus and cortex, but did not beneficially affect hyperglycemia and hypoinsulinemia in the STZ-induced diabetic mice compared with untreated diabetic mice. Taken together, our findings suggest that telmisartan ameliorates memory deficits in type 1 diabetic mice, at least partly because of attenuation of amyloidosis in the brain.

Telmisartan attenuates monocrotaline-induced pulmonary artery endothelial dysfunction through a PPAR gamma-dependent PI3K/Akt/eNOS pathway

BackgroundPulmonary artery endothelial dysfunction has been demonstrated in pulmonary arterial hypertension (PAH). Telmisartan has beneficial effects in endothelial function in PAH patients; however, the underlying mechanisms for these effects remain unknown. AimsIn this study, we observed the effects of telmisartan on monocrotaline (MCT)-induced Sprague Dawley (SD) rat model of PAH. MethodsAfter a single-dose injection of MCT (60 mg/kg), oral administration of telmisartan (10 mg/kg/d) was started from day 1 to day 28 or with saline as MCT control. The vasorelaxation and remodelling of pulmonary arteries; the expression of peroxisome proliferator-activated receptor γ (PPARγ), Akt, eNOS; levels of phosphorylation of Akt (p-Akt) and phosphorylation of eNOS (p-eNOS) were analysed in isolated rat pulmonary arteries and cultured human pulmonary artery endothelial cells (HPAECs). ResultsCompared to MCT control group, telmisartan treatment ameliorated pulmonary artery endothelial dysfunction and remodelling, prevented the elevation of right ventricular systolic pressure (RVSP) induced by MCT. Immunoblotting results indicated lower levels of PPARγ, p-Akt and p-eNOS in pulmonary arteries treated with MCT alone and levels were significantly restored by co-treatment with telmisartan. In isolated pulmonary arteries, the impaired endothelium-dependent vasorelaxation of pulmonary arteries was improved following incubation with telmisartan for 12 h, whereas this effect was blocked by the inhibition of either PPARγ or phosphoinositide 3-kinase (PI3K) signals transduction. In cultured HPAECs, treatment with telmisartan increased PPARγ expression and promoted the phosphorylation of Akt and eNOS, thereby increasing the production of NO. These effects were abolished by the inhibition of PPARγ or PI3K. ConclusionTelmisartan protected against endothelial dysfunction in MCT-induced PAH through a PPARγ-dependent PI3K/Akt/eNOS pathway. Thus, telmisartan may be a promising therapeutic strategy for patients with a high risk of PAH.

Administration of Telmisartan Reduced Systolic Blood Pressure and Oxidative Stress Probably Through the Activation of PI3K/Akt/eNOS Pathway and NO Release in Spontaneously Hypertensive Rats

We investigated the effects of telmisartan, the blocker of angiotensin II receptor 1, on the regulation of systolic blood pressure (SBP) and oxidative stress through endothelial nitric oxide (NO) release in spontaneously hypertensive rats (SHRs). SHRs randomly received placebo, oral feeding of telmisartan (5 mg/kg or 10 mg/kg) every day and Wistar-Kyoto rats (WKYs) served as normotensive control. The SBP of rat was measured before and weekly thereafter. After a total of 8-week treatment, rats were killed for experimental measurements. Parameters that subject to measurements in isolated aorta endothelial cells include: NO concentration, protein expression levels of angiotensin II receptor 1, nitrotyrosine, 8-isoprostane, SOD, PI3K, Akt, AMPK and eNOS. In addition, L-NMMA, a general inhibitor of nitric oxide synthase, was also applied to test the inhibition of NO concentration. We found that SBPs were significantly lower in telmisartan therapy group than in placebo treated hypertensive rats and WKYs (p<0.05). The NO concentration was significantly higher in telmisartan-treated group with increased activity of the PI3K/Akt pathway and activated eNOS signaling. Blockade of Akt activity reversed such effects. Activation of AMPK also contributed to the phosphorylation of eNOS. L-NMMA treatment reduced less NO concentration in SHR rats than the telmisartan co-treated groups. Oxidative stress in SHRs was also attenuated by telmisartan administration, shown by reduced formation of nitrotyrosine, 8-isoprostane, and recovered SOD protein level. Telmisartan enhanced NO release by activating the PI3K/Akt system, AMPK phosphorylation and eNOS expression, which attenuated the blood pressure and oxidative stress in SHRs.

Acute regulation of pancreatic islet microcirculation and glycaemia by telmisartan and ramipril: discordant effects between normal and Type 2 diabetic rats

Diabetic patients are often treated with an ACEi (angiotensin-converting enzyme inhibitor) or angiotensin receptor antagonist against hypertension or albuminuria. These drugs also have a positive impact on glucose tolerance, but the mechanism for this remains elusive. Hypothesizing a positive non-additive effect, we studied whether the angiotensin receptor antagonist telmisartan or the ACEi ramipril acutely influence insulin secretion and glycaemia in vivo in healthy and Type 2 diabetic rats through effects on islet blood perfusion. Telmisartan and ramipril were injected intravenously into anaesthetized non-diabetic Wistar rats or Type 2 diabetic GK (Goto-Kakizaki) rats. In non-diabetic Wistar rats, neither whole PBF (pancreatic blood flow) nor IBF (islet blood flow) were significantly influenced by telmisartan and ramipril, alone or in combination. Renal blood flow was enhanced significantly by telmisartan and ramipril when used in combination, whereas ABF (adrenal blood flow) was not affected by any of the drugs. Telmisartan and ramipril both significantly increased serum insulin levels, but did not influence glycaemia. In Type 2 diabetic GK rats, both whole PBF and IBF were significantly decreased by telmisartan and ramipril, but only when used in combination. Renal blood flow was enhanced significantly by telmisartan and ramipril alone, but not when used in combination, whereas ABF was not affected by any of the drugs. Telmisartan and ramipril both significantly decreased serum insulin levels, and non-additively elevated blood glucose levels. In conclusion, the present study suggests that a local pancreatic RAS (renin-angiotensin system), sensitive to acute administration of telmisartan and ramipril, controls pancreatic IBF and insulin secretion and thereby has an impact on glucose tolerance. Our findings indicate unexpected significant differences in the effects of these agents on islet microcirculation, in vivo insulin secretion and glycaemia between healthy and Type 2 diabetic rats.

Protective effect of telmisartan on water imbalance following bilateral ureteral obstruction in rats

Objective To explore the molecular mechanism of renal function defects after bilateral ureteral obstruction (BUO) and investigate the effect of telmisartan (TEL) on the expression of renal aquaporin 2 following BUO in rats.Methods Thirty-six Munich-Wistar rats were randomly divided into three groups (BUO,n =12 ; TEL,n =12 ; Sham,n =12).The BUO model was built in BUO and TEL groups by bilateral ureteral ligation.Age-and time-matched sham-operated controls were prepared.The rats in TEL group were fed on TEL [5 mg/(kg·d)] every day.BUO was released 24 h after BUO,and at the 4th day the blood samples were collected and kidneys were harvested to examine the effects of TEL on the dysregulation of AQP2 by using semi quantitative immunoblottling and immunohistochemistry.Results BUO resulted in a marked polyuria [BUO vs.sham:(93 ±6) μL/(min·kg) vs.(26 ±4) μ/(min·kg),n =12;P＜0.05] and a reduced urine specific gravity [BUO vs.sham:1.007 ±0.007 vs.1.024 ±0.017,n =12;P ＜0.05] and urine Na [(43.25 6.99) mmol/L vs.(182.37 ± 17.91) mmol/L,n =12 ; P ＜ 0.05],an increased Scr [(66.22 ±6.03) μmol/L vs.(33.89 ±2.97) μmol/L,n =12;P ＜0.05] and serum potassium [(5.57 0.37) mmol/L vs.(4.29 ±0.09) mmol/L,n =12;P ＜0.05].Administration of TEL partly prevented this increase in postobstructive urine production [(54 ±6) vs.(93 ±6) μL/(min·kg),n =12;P ＜0.05],and decrease in urine specific gravity (1.017 ± 0.009 vs.1.007 ± 0.007,n =12 ; P ＜ 0.05).TheScr and serum potassium levels were lower significantly in TEL group than in BUO group [(42.83 1.51)μmol/Lvs.(66.22 6.03) μmol/L; (4.69 ±0.21) mmol/L vs.(5.57 ±0.37) mmol/L,n=12;P＜0.05].BUO resulted in a significantly decreased expression of AQP2 as compared with controls,and TEL prevented the reduction of AQP2 (P ＜ 0.05).Conclusion TEL prevents dysregulation of AQP2 in response to BUO,demonstrating a marked renoprotective effect of TEL treatment in conditions with urinary tract obstruction. Key words: Ureteral obstruction ; Aquaporin 2 ; Telmisartan ; Renal function

Telmisartan Improves Insulin Resistance of Skeletal Muscle Through Peroxisome Proliferator–Activated Receptor-δ Activation

The mechanisms of the improvement of glucose homeostasis through angiotensin receptor blockers are not fully elucidated in hypertensive patients. We investigated the effects of telmisartan on insulin signaling and glucose uptake in cultured myotubes and skeletal muscle from wild-type and muscle-specific peroxisome proliferator–activated receptor (PPAR) δ knockout (MCK-PPARδ−/−) mice. Telmisartan increased PPARδ expression and activated PPARδ transcriptional activity in cultured C2C12 myotubes. In palmitate-induced insulin-resistant C2C12 myotubes, telmisartan enhanced insulin-stimulated Akt and Akt substrate of 160 kDa (AS160) phosphorylation as well as Glut4 translocation to the plasma membrane. These effects were inhibited by antagonizing PPARδ or phosphatidylinositol-3 kinase, but not by PPARγ and PPARα inhibition. Palmitate reducing the insulin-stimulated glucose uptake in C2C12 myotubes could be restored by telmisartan. In vivo experiments showed that telmisartan treatment reversed high-fat diet–induced insulin resistance and glucose intolerance in wild-type mice but not in MCK-PPARδ−/− mice. The protein levels of PPARδ, phospho-Akt, phospho-AS160, and Glut4 translocation to the plasma membrane in the skeletal muscle on insulin stimulation were reduced by high-fat diet and were restored by telmisartan administration in wild-type mice. These effects were absent in MCK-PPARδ−/− mice. These findings implicate PPARδ as a potential therapeutic target in the treatment of hypertensive subjects with insulin resistance.

Renoprotective mechanisms of telmisartan on renal injury and inflammation in SHRSP.Z-Leprfa/IzmDmcr rats

SHRSP.Z-Lepr(fa)/IzmDmcr (SHRSP fatty) rats create a new animal model of metabolic syndrome. However, the renoprotective effect of telmisartan therapy and its underlying mechanisms in SHRSP fatty rats remain unknown. We evaluate the effects of long-term telmisartan therapy on renal dysfunction, podocyte injury, inflammation, and transforming growth factor-β1 (TGF-β1)/Smad, epithelial-mesenchymal transition (EMT), mitogen-activated protein kinase (MAPK), Rho-kinase, and cell-cycle progression pathway in the renal cortex of SHRSP fatty rats. Seven-week-old male SHRSP fatty rats were treated with vehicle, telmisartan, and hydralazine for 8 weeks. Age-matched male Wistar-Kyoto/Izumo rats served as a control group. Vehicle-treated SHRSP fatty rats developed proteinuria and renal dysfunction, which in the telmisartan group was less than the vehicle and hydralazine group without changing blood pressure. Glomerulosclerosis and interstitial fibrosis were impaired in SHRSP fatty rats, and the renal damage in the telmisartan group was less than the vehicle and hydralazine groups. Decreased expression of nephrin and podocin and increased desmin-positive area in SHRSP fatty rats were restored by telmisartan but not hydralazine. TGF-β1/Smad, EMT marker, MAPK, Rho-kinase, and cell-cycle progression pathways were upregulated in SHRSP fatty rats, and these increased proteins in the telmisartan group were less than the vehicle and hydralazine group. Telmisartan administration resulted in significant suppression in tumor necrosis factor-α expression and nuclear factor-κB phosphorylation. Long-term telmisartan therapy may improve renal dysfunction, glomerulosclerosis, podocyte injury, and inflammation associated with EMT, TGF-β/Smad, MAPK, Rho-kinase pathway in SHRSP fatty rats. Thus, telmisartan may have significant therapeutic potential for metabolic syndrome.

508 EFFECT OF ANTIHYPERTENSIVE TREATMENT ON MORNING BLOOD PRESSURE SURGE. DETAILED ASSESSMENT BY COMBINATION OF 24 H AMBULATORY BLOOD PRESSURE MONITORING AND POLYSOMNOGRAPHY

Background: The rate of morning blood pressure rise, appears to significantly contribute to the higher morning incidence of cardiovascular events. Aim of our study was to compare the effects of once a day administration of Telmisartan (T) and Valsartan (V) in patients with mild to moderate hypertension, according to a randomized, double-blind design. Sleep was objectively quantified by polysomnography. Methods: 31 consecutive patients with essential hypertension were enrolled. Patients underwent 24 h ambulatory (A) BP monitoring and full polysomnography combined with beat by beat BP monitoring, under placebo (P), T 80 mg and V 160 mg. Results: At the end of each 2 month treatment period the rate of patients with controlled ASBP and ADBP with T and V, respectively, was 95% vs 50% for early morning hours; 62% vs 37% for 24 h ABP; 69% vs 31% for daytime ABP and 69% vs 50% for night-time ABP, (all T-to-V differences p < 0.05). The corresponding rates of ABP normalization with P were 50% for early morning hours, 0% for 24 h, 12% for daytime,14% for night-time ABP. The rate of clinic BP normalization was 81% vs 62% with T vs V respectively (p < 0.05). The proportion of dippers was 69% with P, 75% with T and 56% with V (T vs P and T vs V p < 0.05). Conclusions: T administration offered a significantly better clinic and 24 h ABP control than either P or V, also when focusing on early morning hours. T on morning administration was also associated with greater ABP dipping rate than P or V.

Investigations into mild electric foot shock stress-induced cognitive enhancement: possible role of angiotensin neuropeptides

This study was designed to investigate the role of angiotensin neuropeptides in mild electric foot shock stress-induced cognitive enhancement in mice. Mild stress was induced by applying mild electric foot shocks of 0.15 mA intensity for 0.5 s. The stress-induced alteration in cognition was assessed using a Morris water maze test. The animals were subjected to mild electric foot shocks 5 min before we recorded escape latency time (ELT), an index of learning, during the first 4 days of a 5-day trial in the Morris water maze. The time spent in target quadrant (TSTQ), an index of retrieval, was noted on the fifth day without prior administration of electric foot shock. The angiotensin-converting enzyme inhibitor lisinopril (5, 10 and 20 mg/kg), and telmisartan (1, 2 and 5 mg/kg), an angiotensin II receptor blocker, were employed to assess the role of angiotensin neuropeptides. The application of mild electric shocks significantly decreased ELT and increased TSTQ, indicating enhancement in stress-induced learning and memory. However, administration of lisinopril and telmisartan significantly attenuated the stress-induced decrease in ELT and increase in TSTQ. It may be concluded that mild electric foot shock-induced stress triggers the release of angiotensin neuropeptides that may be responsible for memory enhancement.

Dynamic Analysis of Pharmacokinetics of Orally Administered Drugs Using Positron Emission Tomography

Positron emission tomography (PET) is a powerful and noninvasive technology for molecular imaging in living systems. Its high sensitivity and high spatial-temporal resolution make this technology particularly useful to analyze the disposition of drugs in the body. PET technology could be applied to analyze the process of distribution of orally administered drugs on the basis of time-profiles of radioactivity in vivo. Kinetic analysis of radioactivity derived from 18F-labeled 2-fluoro-2-deoxy-D-glucose administered orally to rats under several conditions indicated that not only gastric emptying and intestinal transit but also the rate constant of intestinal absorption and limited process of oral absorption could be evaluated quantitatively. After oral administration of 11C-labeled telmisartan with or without non-radiolabeled telmisartan, systemic bioavailability and hepatic distribution of radioactivity significantly increased non-linearly with dose. In the intestinal lumen, telmisartan and its glucuronide, converted by UDP-glucuronosyl transferase (UGT), were detected and the ratio of telmisartan decreased at a high dose of telmisartan. In vitro permeation study revealed that telmisartan is a substrate of P-glycoprotein (P-gp). It was reported that hepatic uptake of telmisartan is mediated by organic anion transporting polypeptide 1B3 (OATP1B3) and most of the hepatic radioactivity in the liver is derived from telmisartan. These results indicated that P-gp for intestinal absorption, OATP1B3 for hepatic uptake and UGT for glucuronidation could be considered as limiting steps of orally administered telmisartan. Therefore, PET study is highly anticipated to be a potent tool for better understanding of gastrointestinal absorption and the subsequent tissue distribution of various drugs and candidates.

Effect of Angiotensin II Receptor Antagonist Telmisartan on Detrusor Overactivity in Rats With Bladder Outlet Obstruction

To investigate the changes of expression in both the nerve growth factor (NGF) and the angiotensin II type 1 (AT1) receptors in the urothelium and the detrusor muscle in a rat model of bladder outlet obstruction (BOO). To determine whether the AT1 receptor antagonist telmisartan alleviated the detrusor overactivity in rats with BOO. Male Sprague-Dawley rats were randomly assigned to 3 groups. The control group (n = 10) was sham-operated. The animals in the BOO (n = 20) and the telmisartan groups (n = 20) underwent a partial BOO operation. The telmisartan group received telmisartan (3 mg/kg/d) for 14 days. Cystometry was performed in all 3 groups for 2 weeks after surgery. The expression levels and the cellular distribution of NGF and AT1 receptors were quantified by Western blot analysis and immunofluorescence staining. On cystometry, the intercontraction interval was shorter and the mean number of nonvoiding contractions was increased in the BOO group, compared with those in the control group. The intercontraction interval was longer and the number of nonvoiding contractions was reduced in the telmisartan group, compared with those in the BOO group. In Western blotting and immunofluorescence staining, we found that the expression and the immunoreactivity of NGF and the AT1 receptors were increased in the BOO group, compared with those in the control group. However, with oral administration of telmisartan, those of NGF and AT1 were decreased. The AT1 receptors may play a significant role in the pathogenesis of the detrusor overactivity in a rat model of BOO.

Peroxisome Proliferator-Activated Receptor-γ Activation With Angiotensin II Type 1 Receptor Blockade Is Pivotal for the Prevention of Blood-Brain Barrier Impairment and Cognitive Decline in Type 2 Diabetic Mice

We reported previously that an angiotensin II type 1 receptor blocker, telmisartan, improved cognitive decline with peroxisome proliferator-activated receptor-γ activation; however, the detailed mechanisms are unclear. Enhanced blood-brain barrier (BBB) permeability with alteration of tight junctions is suggested to be related to diabetes mellitus. Therefore, we examined the possibility that telmisartan could attenuate BBB impairment with peroxisome proliferator-activated receptor-γ activation to improve diabetes mellitus-induced cognitive decline. Type 2 diabetic mice KKA(y) exhibited impairment of cognitive function, and telmisartan treatment attenuated this. Cotreatment with GW9662, a peroxisome proliferator-activated receptor-γ antagonist, interfered with these protective effects of telmisartan against cognitive function. BBB permeability was increased in both the cortex and hippocampus in KKA(y) mice. Administration of telmisartan attenuated this increased BBB permeability. Coadministration of GW9662 reduced this effect of telmisartan. Significant decreases in expression of tight junction proteins and increases in matrix metalloproteinase expression, oxidative stress, and proinflammatory cytokine production were observed in the brain, and treatment with telmisartan restored these changes. Swollen astroglial end-feet in BBB were observed in KKA(y) mice, and this change in BBB ultrastructure was decreased in telmisartan. These effects of telmisartan were weakened by cotreatment with GW9662. In contrast, administration of another angiotensin II type 1 receptor blocker, losartan, was less effective compared with telmisartan in terms of preventing BBB permeability and astroglial end-foot swelling, and coadministration of GW9662 did not affect the effects of losartan. These findings are consistent with the possibility that, in type 2 diabetic mice, angiotensin II type 1 receptor blockade with peroxisome proliferator-activated receptor-γ activation by telmisartan may help with protection against cognitive decline by preserving the integrity of the BBB.

Modulation of urinary peptidome in humans exposed to high altitude hypoxia

The exposure of healthy subjects to high altitude represents a model to explore the pathophysiology of diseases related to tissue hypoxia and to evaluate pharmacological approaches potentially useful as a therapy for chronic diseases related to hypoxia. We explored the urinary peptidome to detect alterations induced by the exposure of subjects to different altitudes (sea level, high altitude = 3500 m, very high altitude = 5400 m) and to pharmacological treatment. Urine samples were collected from 47 subjects, randomly and blindly assigned to placebo (n = 24) or Telmisartan (n = 23). Samples were purified by the use of magnetic beads, then analysed by MALDI-TOF MS. Results showed that the urinary peptidome is not affected by the administration of Telmisartan, neither at the sea level nor at high and very high altitudes. In contrast, the urinary protein profiles are modified when subjects are exposed to high and very high altitudes, and we detected six peptides differentially expressed in hypobaric hypoxia at high or very high altitude compared to the sea level. Two of them were identified as fragments of the glycoprotein uromodulin and of the α1-antitrypsin. This is the first proteomic study showing that hypobaric hypoxia conditions affect the urinary peptidome.

Ameliorative Effects of Telmisartan on the Inflammatory Response and Impaired Spatial Memory in a Rat Model of Alzheimer’s Disease Incorporating Additional Cerebrovascular Disease Factors

Telmisartan, an angiotensin type 1 receptor blocker, is used in the management of hypertension to control blood pressure. In addition, telmisartan has a partial agonistic effect on peroxisome proliferator activated receptor γ (PPARγ). Recently, the effects of telmisartan on spatial memory or the inflammatory response were monitored in a mouse model of Alzheimer's disease (AD). However, to date, no studies have investigated the ameliorative effects of telmisartan on impaired spatial memory and the inflammatory response in an AD animal model incorporating additional cerebrovascular disease factors. In this study, we examined the effect of telmisartan on spatial memory impairment and the inflammatory response in a rat model of AD incorporating additional cerebrovascular disease factors. Rats were subjected to cerebral ischemia and an intracerebroventricular injection of oligomeric or aggregated amyloid-β (Aβ). Oral administration of telmisartan (0.3, 1, 3 mg/kg/d) seven days after ischemia and Aβ treatment resulted in better performance in the eight arm radial maze task in a dose-dependent manner. Telmisartan also reduced tumor necrosis factor α mRNA expression in the hippocampal region of rats with impaired spatial memory. These effects of telmisartan were antagonized by GW9662, an antagonist of PPARγ. These results suggest that telmisartan has ameliorative effects on the impairment of spatial memory in a rat model of AD incorporating additional cerebrovascular disease factors via its anti-inflammatory effect.

An Angiotensin II Type 1 Receptor Blocker Prevents Renal Injury via Inhibition of the Notch Pathway in Ins2 Akita Diabetic Mice

Recently, it has been reported that the Notch pathway is involved in the pathogenesis of diabetic nephropathy. In this study, we investigated the activation of the Notch pathway in Ins2 Akita diabetic mouse (Akita mouse) and the effects of telmisartan, an angiotensin II type1 receptor blocker, on the Notch pathway. The intracellular domain of Notch1 (ICN1) is proteolytically cleaved from the cell plasma membrane in the course of Notch activation. The expression of ICN1 and its ligand, Jagged1, were increased in the glomeruli of Akita mice, especially in the podocytes. Administration of telmisartan significantly ameliorated the expression of ICN1 and Jagged1. Telmisartan inhibited the angiotensin II-induced increased expression of transforming growth factor β and vascular endothelial growth factor A which could directly activate the Notch signaling pathway in cultured podocytes. Our results indicate that the telmisartan prevents diabetic nephropathy through the inhibition of the Notch pathway.

Pilot data on telmisartan short‐term effects on glucose metabolism in the olfactory tract in Alzheimer's disease

The possible effect of antihypertensive therapy on Alzheimer's disease (AD) has been studied, and angiotensin II receptor blockers (ARBs) have been suggested to exert an effect on cognitive decline. The purpose of this study is to clarify the functional effects of telmisartan, a long-acting ARB, on AD brain using prospective longitudinal 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) studies. For this purpose, brain glucose metabolism of four hypertensive patients with AD was examined with FDG-PET before and after administration of telmisartan. Studied subjects underwent three FDG-PET studies at intervals of 12 weeks. Antihypertensive treatment except for telmisartan was started after the first FDG-PET and continued for 24 weeks. Then 40–80 mg of telmisartan was added after the second FDG-PET and continued for 12 weeks.Glucose metabolism was significantly decreased during the first 12 weeks without telmisartan use at an area (−10, 21, −22, x, y, z; Z = 3.56) caudal to the left rectal gyrus and the olfactory sulcus corresponding to the left olfactory tract. In contrast, the introduction of telmisartan during the following 12 weeks preserved glucose metabolism at areas (5, 19, −20, x, y, z; Z = 3.09; 6, 19, −22, x, y, z; Z = 2.88) caudal to the bilateral rectal gyri and olfactory sulci corresponding to the bilateral olfactory tracts. No areas showed decreased glucose metabolism after the introduction of telmisartan. In AD, amyloid-β deposition is observed in the anterior olfactory nucleus (AON) of the olfactory tract. Glucose metabolism in AON may be progressively decreased and preserved by telmisartan.

Attenuation of Immune-Mediated Renal Injury by Telmisartan, an Angiotensin Receptor Blocker and a Selective PPAR-γ Activator

Background/Aims: Anti-glomerular basement membrane (GBM) nephritis is characterized by activation of the renin-angiotensin system. This study aimed to determine the question of whether a temporary angiotensin II blockade at the initial stage of anti-GBM nephritis is able to attenuate the disease as well as differences in renoprotection among angiotensin II receptor blockers (ARBs) with distinct peroxisome proliferator-activated receptor (PPAR)-γ-modulating activities. Methods: C57BL/6J mice were immunized with rabbit IgG, followed by intravenous injection of rabbit anti-mouse antibodies. Mice were then treated with telmisartan, losartan, and telmisartan + GW9662 (a PPAR-γ antagonist) for 5 days, or hydralazine for 9 days. On days 8 and 13, mice were sacrificed to obtain tissues for histological analysis. Results: The temporary administration of telmisartan significantly suppressed glomerular damage compared to hydralazine. Losartan showed a similar effect but was less effective. Co-administration of GW9662 attenuated the renoprotective effect of telmisartan, almost to levels observed with losartan. In particular, it limited the decreased infiltration of inflammatory cells and preservation of capillaries in the glomeruli induced by telmisartan. Conclusion: Temporary angiotensin II blockade at the initial stage of anti-GBM disease dramatically inhibited its progression. In addition to a class effect of ARBs, telmisartan modified inflammation and endothelial damage in the kidney through its PPAR-γ-agonistic action.