Abstract 4890: Telmisartan Decreases Sympathetic Nerve Activity via Reduction in Oxidative Stress Through the Blockade of AT1 Receptor in the Vasomotor Center in Dietary-induced Obesity Rat

Abstract

Background: Activation of sympathetic nerve activity (SNA) is critically involved in the occurrence of hypertension in metabolic syndrome (MetS). However, the mechanism(s) involved remains unknown. Reactive oxygen species (ROS) generation in the brain may elicit sympathoexcitation in MetS. The rostral ventrolateral medulla (RVLM) is the vasomotor center that determines basal central sympathetic outflow. ROS in the RVLM is produced mainly by NAD (P) H oxidase via angiotensin II type 1 receptor stimulation (AT 1 R). The present study aimed to determine whether telmisartan decreases SNA via a reduction in ROS through the blockade of AT 1 R in the RVLM of MetS model rats. Methods and Results: Male Sprague-Dawley rats were fed a high-fat diet and segregated into obesity-prone (OP, n = 5) and obesity-resistant (OR, n = 5) groups based on their body weight (BW) after 13 weeks. The OP group was then divided into 2 groups, OP with telmisartan (5mg/kg/day for 12 weeks, TLM-OP, n = 3) and OP without telmisartan (VEH-OP, n = 3). At 13 weeks, body weight (BW), systolic blood pressure (SBP), heart rate (HR), and urinary norepinephrine excretion (uNE) as a parameter of SNA were significantly higher in OP than in OR (BW; 760 ± 46g vs 548 ± 13g, SBP; 151 ± 5mmHg vs 123 ± 7mmHg, HR; 375 ± 11bpm vs 333 ± 5bpm, uNE; 0.35 ± 0.05 μ g/day/kg vs 0.25 ± 0.04 μ g/day/kg, n = 5 for each, P < 0.05 for each). ROS in the RVLM, measured by the thiobarbituric acid-reactive substances (TBARS) method, was significantly higher in OP than in OR (7.2 ± 0.8 μ mol/g vs 2.2 ± 1.9 μ mol/g wet wt, n = 4 each, P < 0.05). Microinjection of AT 1 R blocker (ARB), candesartan, into the RVLM induced a significantly greater mean SBP reduction in OP than in OR. The expression of angiotensinogen, angiotensin-converting enzyme (ACE), and AT 1 R in the RVLM assessed by Affymetrix microarray was significantly higher in OP than in OR. TLM-OP had significantly lower BW, SBP, HR, uNE, and TBARS than VEH-OP. Microinjection of angiotensin II into the RVLM resulted in significantly lower pressor responses in TLM-OP than in VEH-OP. Conclusion: In MetS, increased ROS in the RVLM produced by upregulation of the local renin-angiotensin system increases SNA. Telmisartan inhibits SNA via a reduction of ROS through the blockade of AT 1 R in the RVLM.