Effect of Telmisartan, Angiotensin II Receptor Antagonist, on Metabolic Profile in Fructose-Induced Hypertensive, Hyperinsulinemic, Hyperlipidemic Rats

135 Hypertens Res Vol.31 (2008) No.1 p.123-128 Original Article Effect of Telmisartan, Angiotensin II Receptor Antagonist, on Metabolic Profile in FructoseInduced Hypertensive, Hyperinsulinemic, Hyperlipidemic Rats Yehuda KAMARI1),2), Ayelet HARARI2), Aviv SHAISH2), Edna PELEG1), Yehonatan SHARABI1), Dror HARATS2), and Ehud GROSSMAN1) The metabolic syndrome (MS) is a common risk factor for cardiovascular disease and type-2 diabetes. Recently, telmisartan, an angiotensin II receptor antagonist that has an antihypertensive effect, has been reported to be a partial peroxisome proliferator–activated receptor γ (PPARγ) agonist. The anti-diabetic hormone adiponectin has been recognized as a marker of in vivo PPARγ activation. Therefore, we studied telmisartan’s effect on the metabolic profile and adiponectin levels in a fructose-induced hypertensive, hyperinsulinemic, hyperlipidemic rat model. Twenty-four male Sprague-Dawley rats were divided into three groups (eight in each). One group of control rats was fed standard chow for 5 weeks while a second was fed a fructose-enriched diet. A third group was fed a fructose-enriched diet for 5 weeks and treated with telmisartan 5 mg/kg/day during the last 2 weeks. Fructose feeding increased systolic blood pressure (mean± SEM), from 130 ± 1 to 148 ± 2 mmHg, insulin from 0.26 ± 0.03 to 0.68 ± 0.08 ng/mL, and triglycerides from 102 ± 6 to 285 ± 23 mg/dL (p < 0.05 for all variables). Telmisartan treatment reversed these effects and reduced blood pressure to 125 ± 2 mmHg, insulin levels to 0.41 ± 0.07 ng/mL, and triglycerides to 146 ± 18 mg/dL (p < 0.05 for all variables), while attenuating the increase in body weight during weeks 3 to 5. In contrast, telmisartan did not affect plasma adiponectin levels. In conclusion, although telmisartan is considered a partial PPARγ agonist, its beneficial effect in the fructose-induced hypertension, hypertriglyceridemia, and hyperinsulinemia rat model is apparently not mediated by adiponectin elevation but rather by direct inhibition of AT1 receptor. (Hypertens Res 2008; 31: 135–140) Key Words: metabolic syndrome, telmisartan, adiponectin, peroxisome proliferator–activated receptor γ Introduction The metabolic syndrome (MS), characterized by the clustering of hypertension, insulin resistance, and dyslipidemia, is a common risk factor for cardiovascular disease and type-2 diabetes (1, 2). To achieve optimal prevention of cardiovascular outcomes in hypertensive patients, a multi-factorial approach is required, combining lifestyle modification, blood pressure lowering, and control of dyslipidemia. In addition, prevention of type-2 diabetes has become recognized as an important component of cardiovascular risk reduction in patients with essential hypertension (3, 4). Since insulin resistance is the core malfunction that leads eventually to the development of type-2 diabetes, improving insulin sensitivity can be beneficial and contribute to lowering the risk for developing diabe- From the 1)Hypertension Unit and 2)Institute of Lipid and Atherosclerosis Research, Sheba Medical Center, Tel Hashomer and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Address for Reprints: Ehud Grossman, M.D., Internal Medicine D and Hypertension Unit, The Chaim Sheba Medical Center, Tel Hashomer 52621, Israel. E-mail: Received March 27, 2007; Accepted in revised form August 5, 2007. 136 Hypertens Res Vol. 31, No. 1 (2008) tes. Activation of the renin-angiotensin system (RAS) contributes to the development of insulin resistance. β-Cell dysfunction due to angiotensin-mediated increases in oxidative stress, inflammation, and free fatty acids concentrations, as well as glucotoxicity, lipotoxicity, and advanced glycation, potentially contribute to insulin resistance related to RAS activation (5). Although a number of clinical and experimental studies suggested that angiotensin II receptor antagonists can improve insulin sensitivity and decrease the incidence of new-onset type-2 diabetes in patients with hypertension, the exact mechanisms underlying these beneficial effects are not fully understood (6–8). Adiponectin has been shown to have insulin-sensitizing properties in murine models (9–13). Several studies have shown that some of the beneficial effects of peroxisome proliferator–activated receptor γ (PPARγ) activation are mediated by the increase in adiponectin levels (14, 15). A few recent studies found that telmisartan, an angiotensin II type 1 (AT1) receptor antagonist, is a partial PPARγ nuclear receptor agonist (16–19). However, there are conflicting data regarding telmisartan’s in vivo effects on metabolic parameters in animal models of the metabolic syndrome (16, 20). Therefore, we assessed telmisartan’s effects on adiponectin and metabolic indices in fructose-induced hypertensive, hyperinsulinemic, hyperlipidemic rats. Methods Twenty-four male Sprague-Dawley rats weighing 220 to 250 g were used in the study. A control group (n= 8) was fed a normal chow diet. Sixteen rats were fed a fructose-enriched diet (Teklad-Harlan, Madison, USA) consisting of 21% protein, 5% fat, 60% carbohydrate, 0.49% sodium, and 0.49% potassium, for 5 weeks. The rats fed the fructose-enriched diet (FED) were further subdivided into two groups: one group of 8 rats was given FED for 5 weeks (nontreated group) while the other group of 8 rats was given FED for 5 weeks, with telmisartan 5 mg/kg/day administered in the last 2 weeks of the experiment (treated group). The experiments were conducted according to the Guidelines for Animal Care and Treatment of the hospital’s Animal Ethics Committee. The rats were maintained in a temperature-controlled room (22°C) and kept on a 14/10 light/dark cycle. Telmisartan was administered by dissolving the commercially available drug in the drinking water at an initial concentration of 40 mg/L. Because fluid intake was not scaled linearly with body weight, drug intake based on body weight tended to decline over time. Therefore, the drug concentration in the drinking water was increased during the course of the study every week to maintain the scheduled dosing. The fluid intake was similar in all the groups. Body weight was measured before the start of the experiment and then weekly. Systolic blood pressure (SBP) was measured weekly in conscious rats by the indirect tail-cuff method using an electrosphygmo- manometer and a pneumatic pulse transducer (Narco Biosystems, Houston, USA). The mean of five consecutive readings was recorded. Blood samples from a retro-orbital sinus puncture were taken, under light anesthesia with isoflurane after 5 h of fasting, at the beginning of the experiment and after 3 and 5 weeks. Plasma adiponectin concentrations were determined using an RIA kit (Linco Research, Billerica, USA). Insulin levels were assessed using a rat insulin ELISA kit (Mercodia, Uppsala, Sweden), and triglyceride levels were assayed with an automated analyzer of an enzymatic color (...truncated)