Comparative analysis of telmisartan and olmesartan on cardiac function in the transgenic (mRen2)27 rat

Abstract

Telmisartan, an angiotensin receptor blocker, may have unique benefits as it possesses partial peroxisome proliferator-activated receptor (PPAR)-␥ agonist activity in addition to antihypertensive effects. In this study, we test whether treatment with telmisartan ameliorates cardiovascular abnormalities to a greater extent than olmesartan, which has little PPAR-␥ activity. The hypertensive rodent model of tissue renin-angiotensin system activation, transgenic (mRen2)27 (Ren2) rats and their littermate Sprague-Dawley controls were used. Rats were treated with telmisartan (2 mg·kg Ϫ1 ·day Ϫ1 ), olmesartan (2.5 mg·kg Ϫ1 ·day Ϫ1 ), or vehicle via drinking water for 3 wk; these doses achieved similar blood pressure control, as measured by telemetry. Ren2 rats displayed impaired diastolic and systolic function using left ventricular (LV) pressure-volume (P-V) analysis. Load-independent diastolic indexes, including the time constant of isovolumic relaxation and the slope of the end-diastolic P-V relationship, as well as systolic indexes, including preload recruitable stroke work, the dP/dt max-end-diastolic volume (EDV) relationship, and the P-V area-EDV relationship, were elevated in Ren2 rats compared with Sprague-Dawley controls (P Ͻ 0.05). The Ren2 myocardium exhibited parallel increases in the oxidant markers NADPH oxidase and 3-nitrotyrosine. The increase in the prohypertrophic protein Jak2 in Ren2 rats was associated with cardiac structural abnormalities using light microscopic and ultrastructural analysis, which included interstitial fibrosis, cardiomyocyte and LV hypertrophy, and mitochondrial derangements. Both angiotensin receptor blockers attenuate these abnormalities to a similar extent. Our data suggest that the beneficial effect of telmisartan and olmesartan on cardiac structure and function may be predominantly pressor-related or angiotensin type 1 receptor dependent in this model of renin-angiotensin system activation. oxidative stress; left ventricular hypertrophy; peroxisome proliferatoractivated receptor-␥; Janus-activated kinase 2; AMP-activated protein kinase NUMEROUS REPORTS have demonstrated a seminal role for ANG II and the associated generation of ROS via NADPH oxidase in the development of myocardial remodeling and that angiotensin type 1 receptor (AT 1 R) blockade improves myocardial remodeling, hypertrophy, and ventricular compliance (4, 5, 31). A molecular modeling study (4) demonstrated a structural similarity between the AT 1 R blocker telmisartan and the peroxisome proliferator-activated receptor (PPAR)-␥ agonists pioglitazone and rosiglitazone. Telmisartan, to a greater extent than other angiotensin receptor blockers (ARB), acts as a partial agonist of PPAR-␥ independently of AT 1 R-blocking effects (4, 27). PPAR-␥ agonism improves insulin sensitivity and inhibits vascular oxidative stress and inflammation (11). In this regard, telmisartan reduces glucose, insulin, and triglyceride levels in a rat model of high-fat diet-induced insulin resistance (4).Some evidence suggests that PPAR-␥ a...

Angiotensin II Activation of mTOR Results in Tubulointerstitial Fibrosis through Loss of N-Cadherin

“…As reported elsewhere [26], there were increases in SBP in the Ren2 rats compared to age-matched SD controls, findings were prevented following 3 weeks of treatment with the AT 1 R blocker telmisartan in the Ren2 rats. There were parallel increases in non-log transformed proteinuria in the Ren2 rats (4.83 ± 0.64 mg/mg urine protein/creatinine) compared to SD controls (1.68 ± 0.29 mg/mg; p < 0.05), and improvement was observed with telmisartan treatment (2.77 ± 0.18 mg/mg; p < 0.05).…”

“…Rats were randomly distributed into the following groups: SD control (SD-C) n = 6, telmisartan-treated SD (SD-T) n = 6, Ren2 control (R2-C) n = 6, and telmisartan-treated Ren2 (R2-T) n = 6. Beginning at 7 weeks of age, treated rats received daily telmisartan (2 mg/kg) or vehicle solution in drinking water for a total of 21 days [26]. …”

“…Systolic blood pressures (SBPs) were obtained on a subset of rats previously reported [26]. At 6 weeks of age, rats were anesthetized and instrumented with a radio telemetric transmitter (TA11PA-C40; Data Sciences, St. Paul, Minn., USA) for blood pressure monitoring.…”

Mineralocorticoid receptor blockade improves diastolic function independent of blood pressure reduction in a transgenic model of RAAS overexpression

“…The hypertrophic activity of cardiomyoctyes may be regulated by numerous interacting factors, including hemodynamic (ventricular overload and high coronary perfusion pressure) as well as humoral (ANG II as well as aldosterone) factors (27,33,41). In our model, the RAAS is activated by elevations in tissue ANG II as well as circulating aldosterone, and results from our previous studies (6,44,45) supports that blockade of the ANG II type 1 receptor (AT 1 R) improves measures of hypertrophy. Therefore, our findings that Sp treatment improves fibrosis but not hypertrophy is not entirely surprising and suggest that tissue ANG II may have a more predominant effect on hypertrophic responses in this model than aldosterone actions on the MR.…”

Abnormal amounts of intracellular calcium regulatory proteins in SHRSP.Z-Leprfa/IzmDmcr rats with metabolic syndrome and cardiac dysfunction

“…Thus, we assume that oxidativenitrative stress induced by angiotensin II is a factor underlying cardiac dysfunction in SHRSP fatty rats. ARBs telmisartan and olmesartan can ameliorate cardiac structure and function because of suppression of oxidative stress in a hypertensive rat model of tissue renin-angiotensin system activation (DeMarco et al 2011). In addition, peroxynitrite, a highly effective oxidant, has been shown to inhibit PLB phosphorylation (Kohr et al 2008) and to increase SERCA2a damage (Thomas et al 2011) in cardiomyocytes.…”