Abstract 443: Combining Irbesartan and Trichlormethiazide Elicits Strong Blood Pressure Reduction Associated with Sympathoinhibition and Beneficial Metabolic Profiles in Hypertensive Rats with Metabolic Syndrome

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Background: Sympathoexcitation accompanied by obesity plays a pivotal role in hypertension associated with metabolic syndrome which is characterized by the presence of central obesity, impaired fasting glucose, and dyslipidemia. We have demonstrated that the oxidative stress in the rostral ventrolateral medulla (RVLM) increases sympathetic activity in hypertensive rats. The aim of the present study was to determine whether orally administered angiotensin II receptor blocker (irbesartan; IRB) and diuretics (trichlormethiazide; TCM) decreases blood pressure (BP) via inhibiting sympathetic activity through anti-oxidant effects in the RVLM of spontaneously hypertensive/NDmcr-cp rats (SHR-cp) without eliciting sympathoexcitation due to the strong antihypertensive action. We also investigated the effects of IRB/TCM therapy on the metabolic profile.

Methods and Results: IRB (25 mg/kg/day), TCM (1 mg/kg/day), IRB/TCM (25/1 mg/kg/day) or vehicle; VEH were orally administered for 28 days to SHR-cp (from age of 12 week-old). Each treatment decreased systolic BP (SBP) compared with VEH group (SBP after treatment; IRB 132±1, TCM 147±2, IRB/TCM 118±2 vs. 162±4 mmHg, P<0.01, n=6~7), and IRB/TCM treatment decreased SBP to a greater extent than IRB monotherapy. Both urinary norepinephrine excretion (uNE) as a marker of sympathetic activity and oxidative stress evaluated by thiobarbituric acid-reactive substances (TBARS) levels in the RVLM were decreased in both IRB and IRB/TCM groups compared with VEH group (uNE; 1.1±0.1 and 1.4±0.1 vs. 2.0±0.1μg/day, P<0.01, n=6~7), (TBARS; 0.52±0.02 and 0.54±0.02 vs. 0.73±0.03μmol/g wet wt, P<0.01, n=6~7), but not in TCM group. IRB/TCM treatment did not exert an adverse effect on the metabolic profile, such as fasting blood glucose, total cholesterol, LDL-cholesterol, and HDL-cholesterol, but it decreased the triglyceride levels of SHR-cp compared with VEH group (553±40 vs. 730±37mg/dl, P<0.01, n=6 for each).

Conclusions: These findings suggest that the IRB/TCM combination therapy have a strong antihypertensive effect associated with inhibiting the sympathetic activity reducing oxidative stress in the brain and

preferable metabolic profiles in SHR-cp.

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