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Disparate effects of eplerenone, amlodipine and telmisartan on podocyte injury in aldosterone-infused rats.

ABSTRACT: Several studies in patients with primary aldosteronism (PA) have suggested that aldosterone (ALD) is directly contributing to albuminuria. However, there are limited data pertaining to the direct role of ALD in in vivo models in regard to the induction of renal injury and the involved mechanisms. In the present study, we established a high-dose ALD-infused rat model to evaluate urinary albumin excretion rate (UAER) and podocyte damage. Moreover, we studied the effect of eplerenone (EPL), telmisartan (TEL) and amlodipine (AML) on ALD-induced renal structural and functional changes.Immunohistochemical and real-time PCR analyses, and TUNEL assays were performed to evaluate nephrin expression and podocyte injury.ALD-receiving rats (ARR) showed a progressive increase in BP, UAER and proteinuria when compared with control rats (CR). Conversely, BP was significantly reduced in ALD + EPL (A/ERR)-, ALD + AML (A/ARR)- and ALD + TEL (A/TRR)-treated rats. However, UAER and proteinuria were decreased only in A/ERR and A/TRR, but not in A/ARR. Only EPL administration provided protection against ALD-induced podocyte apoptosis. Renal tissue of ARR revealed enhanced expression of nephrin protein and mRNA. This effect of ALD was inhibited by EPL, but not by TEL or AML. Conclusions. ALD induces direct glomerular injury independent of its haemodynamic effects; this effect of ALD is, at least in part, mediated through activation of the mineralocorticoid receptor.

SUBMITTER: Liang W

PROVIDER: S-EPMC3108348 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Disparate effects of eplerenone, amlodipine and telmisartan on podocyte injury in aldosterone-infused rats.

Liang Wei W Chen Cheng C Shi Jing J Ren Zhilong Z Hu Fengqi F van Goor Harry H Singhal Pravin C PC Ding Guohua G

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 20100820 3

<h4>Background</h4>Several studies in patients with primary aldosteronism (PA) have suggested that aldosterone (ALD) is directly contributing to albuminuria. However, there are limited data pertaining to the direct role of ALD in in vivo models in regard to the induction of renal injury and the involved mechanisms. In the present study, we established a high-dose ALD-infused rat model to evaluate urinary albumin excretion rate (UAER) and podocyte damage. Moreover, we studied the effect of eplere ...[more]

PMID: 20729265

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Project description:A new fixed-dose combination (FDC) formulation of telmisartan 80 mg and S-amlodipine 5 mg (CKD-828) has been developed to increase convenience (as only one tablet is required per day) and improve treatment compliance.The pharmacokinetic characteristics and tolerability of an FDC of telmisartan and S-amlodipine were compared to those after coadministration of the individual agents in this randomized, open-label, single-dose, two-way, four-period, crossover study. To analyze the telmisartan and S-amlodipine plasma concentrations using a validated liquid chromatography-tandem mass spectrometry method, serial blood samples were collected up to 48 hours post-dose for telmisartan and 144 hours post-dose for S-amlodipine, in each period.Forty-eight healthy subjects were enrolled, and 43 completed the study. The mean peak plasma concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to the last measurement (AUC0-t) values of telmisartan were 522.29 ng/mL and 2,475.16 ng·h/mL for the FDC, and 540.45 ng/mL and 2,559.57 ng·h/mL for the individual agents concomitantly administered, respectively. The mean Cmax and AUC0-t values of S-amlodipine were 2.71 ng/mL and 130.69 ng·h/mL for the FDC, and 2.74 ng/mL and 129.81 ng·h/mL for the individual agents concomitantly administered, respectively. The geometric mean ratio (GMR) and 90% confidence interval (CI) for the telmisartan Cmax and AUC0-t (FDC of telmisartan and S-amlodipine/concomitant administration) were 0.8509 (0.7353-0.9846) and 0.9431 (0.8698-1.0226), respectively. The GMR and 90% CI for the S-amlodipine Cmax and AUC0-t (FDC/concomitant administration) were 0.9829 (0.9143-1.0567) and 0.9632 (0.8798-1.0546), respectively. As the intrasubject variability of the Cmax for telmisartan administered individually was 42.94%, all 90% CIs of the GMRs fell within the predetermined acceptance range. Both treatments were well tolerated in this study.CKD-828 FDC tablets were shown to be bioequivalent to coadministration of the individual agents with the respective strength, in healthy subjects under fasting conditions. There was no significant difference in safety profile between the two treatments.

Project description:BackgroundThe efficacy of a combination of a calcium channel blocker (CCB) plus chlorthalidone (diuretic) versus a CCB plus an angiotensin receptor blocker (ARB) in patients not responding to CCB monotherapy has not been evaluated previously. We plan to compare the efficacy and safety of S-amlodipine (CCB) plus chlorthalidone versus S-amlodipine plus telmisartan (ARB) combinations among hypertension patients unresponsive to amlodipine monotherapy.Methods/designThis study is a prospective, randomized, double-blind, multicenter, parallel, non-inferiority phase 4 study. Hypertension patients who have been treated with amlodipine (5 mg) or S-amlodipine (2.5 mg) monotherapy for ≥2 weeks and whose mean diastolic blood pressure (DBP) is greater than 90 mmHg will be randomized to either S-amlodipine (2.5 mg) plus chlorthalidone (25 mg) or S-amlodipine (2.5 mg) plus telmisartan (40 mg) therapy. The primary efficacy endpoint is mean sitting DBP change after 12 weeks of treatment. The study objective is to prove the non-inferiority of the former combination (test drug) as compared to the latter one (control) with a non-inferiority margin of 3 mmHg in mean DBP change. The secondary endpoints are 6-week DBP change, 6- and 12-week sitting systolic BP (SBP) change, and the attainment of the target BP (SBP < 140 mmHg or DBP < 90 mmHg). Urine albumin, albumin/creatinine ratio (ACR), pulse wave velocity, central BP, 24-h ambulatory BP monitoring, and body fluid composition analysis will be performed at each hospital's discretion. The sample size was estimated as 170 in total with 1:1 randomization.DiscussionThis is the first study comparing the efficacy of a CCB plus chlorthalidone versus a CCB plus an ARB in patients who are not responding to CCB single therapy. The study result will help clinicians to choose between chlorthalidone and telmisartan in CCB-unresponsive patients.Trial registrationClinicalTrials.gov , NCT03226340. Registered on 2 December 2015.

Project description:Objective M-bM-^@M-^S Telmisartan, an angiotensin II type 1 (AT1) receptor blocker, and amlodipine, a calcium channel blocker, are antihypertensive agents clinically used as monotherapy or in combination. They exert beneficial cardiovascular effects independently of blood pressure lowering and classic mechanisms of action. In this study, we investigate molecular mechanisms responsible for the off-target effects of telmisartan and telmisartan-amlodipine in endothelial cells (EC), using an unbiased approach. Approach and Results M-bM-^@M-^S In human umbilical vein endothelial cells, microarray analysis of gene expression followed by pathway enrichment analysis and qRT-PCR validation revealed that telmisartan modulates the expression of key genes responsible for cell cycle progression and apoptosis. AmlodipineM-bM-^@M-^Ys effect was similar to control. EC exposed to telmisartan, but not amlodipine, losartan or valsartan, exhibited a dose-dependent impairment of cell growth and failed to enter the S-phase of the cell cycle. Similarly, telmisartan inhibited proliferation in COS-7 cells lacking the AT1 receptor. In telmisartan-treated EC, phosphorylation and activation of Akt as well as MDM2 was reduced, leading to accumulation of p53 in the nucleus, where it represses the transcription of cell cycle promoting genes. Phosphorylation of GSK3M-NM-2 was also reduced, resulting in rapid proteolytic turnover of CyclinD1. Telmisartan induced downregulation of proapoptotic genes and protected EC from serum starvation- and 7-ketocholesterol-induced apoptosis. Conclusions M-bM-^@M-^S Telmisartan exerts antiproliferative and antiapoptotic effects in EC. This may account for the improved endothelial dysfunction observed in the clinical setting. HUVEC were treated with 100 M-BM-5mol/L telmisartan or 5 M-BM-5mol/L amlodipine or both in dimethyl sulfoxide (DMSO) or an equivalent volume of DMSO alone, as control, for 24 hours. Microarray analysis was carried out on two biological replicates per group (total of six samples). See PROTOCOL section for experimental details.

Project description:PurposeHypertension and dyslipidemia are major risk factors for cardiovascular diseases, and reduction of cardiovascular risks can be achieved by combining antihypertensive therapy with statins. The objective of this study was to evaluate the pharmacokinetic interaction between telmisartan/amlodipine fixed dose combination and rosuvastatin in healthy Korean male volunteers.Patients and methodsAn open-label, two-cohort, multiple-dose, single-sequence crossover study was conducted in healthy male subjects. In Cohort 1, the subjects were administered one tablet of telmisartan/amlodipine 80 mg/5 mg once daily for 14 days with or without one tablet of rosuvastatin 20 mg once daily. In Cohort 2, the subjects were administered one tablet of rosuvastatin 20 mg once daily for 14 days with or without one tablet of telmisartan/amlodipine 80 mg/5 mg once daily. Serial blood samples were collected up to 24 hrs post-dose on the 9th and 14th days in Cohort 1 and on the 5th and 14th days in Cohort 2. Plasma drug concentrations were measured by liquid chromatography/tandem mass spectrometry. Pharmacokinetic parameters, including maximum plasma concentration at steady state (Cmax,ss) and area under the plasma concentration versus time curve over dosing interval (AUCτ,ss), were determined by non-compartmental analysis. The geometric least-square mean (GLSM) ratios and associated 90% confidence intervals (CIs) of log-transformed Cmax,ss and AUCτ,ss for separate or concurrent therapy were calculated to evaluate pharmacokinetic interactions.ResultsThirty-eight subjects from Cohort 1 and nineteen subjects from Cohort 2 completed the study. The GLSM ratios and 90% CIs of Cmax,ss and AUCτ,ss, were 0.9829 (0.8334-1.1590) and 1.0003 (0.9342-1.0710) for telmisartan; 0.9908 (0.9602-1.0223) and 1.0081 (0.9758-1.0413) for amlodipine; and 2.2762 (2.0113-2.5758) and 1.3261 (1.2385-1.4198) for rosuvastatin, respectively.ConclusionThe pharmacokinetic parameters of telmisartan/amlodipine, but not rosuvastatin, met the pharmacokinetic equivalent criteria. The increase in systemic exposure to rosuvastatin caused by telmisartan/amlodipine co-administration would not be clinically significant in practice. Nevertheless, an appropriately designed two-sequence crossover study is needed to confirm the results of this study.

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Disparate effects of eplerenone, amlodipine and telmisartan on podocyte injury in aldosterone-infused rats.

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Disparate effects of eplerenone, amlodipine and telmisartan on podocyte injury in aldosterone-infused rats.

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