Abstract 9761: Survival Benefit of Orally Administered Telmisartan in Hypertensive Rats is NOT a Class Effect of Angiotensin II type 1 Receptor Blockers

Abstract

[Backgrounds] Previous studies have suggested that abnormal sympathoexcitation worsen the prognosis of hypertensive heart disease. We have demonstrated, in animal models of hypertension, that brain angiotensin II type 1 receptor (AT1R) induces reactive oxygen species (ROS) and ROS causes sympathoexcitation. We also have demonstrated that orally administered AT1R blocker (ARB) telmisartan, not candesartan, reduces the brain ROS and causes sympathoinhibition via blockade of brain AT1R, despite their similar depressor effects. Previous clinical trials have demonstrated that ARBs have beneficial effects in patients with hypertensive. However, it is not clarified whether the benefits are class-effects or not. The aim of the present study was to determine whether orally administered telmisartan improves survival rate of severely hypertensive rats and whether the benefits were class effects of ARBs or not. [Methods and Results] Angiotensin II-infused (100 ng/kg/day) and salt-loaded (8% NaCl diet) stroke-prone spontaneously hypertensive rats (SHRSP) were divided into telmisartan-treated (TLM), candesartan-treated (CND), and control groups. At 5 weeks after the treatment, both telmisartan and candesartan comparably lowered systolic blood pressure (122±14 mmHg vs. 124±9 mmHg, p=ns) and increased survival rate relative to the control (100%, 100%, and 70%, respectively, n=20 for each). However, brain ROS and urinary norepinephrine excretion (uNE: a marker of sympathoexcitation) were significantly lower in TLM than in CND (brain ROS: 0.8±0.1 μmol/g vs. 1.1±0.1 μmol/g, p<0.01 and uNE: 1.1±0.2 μg/day vs. 1.5±0.2 μg/day, n=20 for each, p<0.05). At 7 weeks, the survival rate was higher in TLM than CND (85% vs. 60%). At 9 weeks no rats survived in CND, whereas 40% survived in TLM. Heart/body weight, left ventricular (LV) end-systolic dimension, and LV wall thickness were significantly lower in TLM than in CND (Heart/body weight; 2.8±0.2 mg/g vs. 3.5±0.1 mg/g, n= 12 and 20, p<0.05). [Conclusion] Orally administered telmisartan prevents LV hypertrophy, preserves LV function and markedly improves survival rate of severely hypertensive rats associated with sympathoinhibition via antioxidant in the brain. These benefits of TLM are not class effects of ARBs.