Sympathoinhibition caused by orally administered telmisartan through inhibition of the AT1 receptor in the rostral ventrolateral medulla of hypertensive rats

Abstract

In patients and animals with hypertension, sympathetic nervous system (SNS) activation is present. We have demonstrated that angiotensin II type 1 receptor (AT 1 R)-induced oxidative stress in the rostral ventrolateral medulla (RVLM), a vasomotor center in the brainstem, causes SNS activation in hypertensive rats. The aim of the present study was to determine whether orally administered AT 1 R blockers (ARBs) inhibit SNS activation through an anti-oxidant effect via inhibition of AT 1 R in the RVLM of hypertensive rats and, if so, whether the benefits are class effects of ARBs. Stroke-prone spontaneously hypertensive rats (SHRSPs), a hypertensive model with sympathoexcitation, were divided into four groups: SHRSPs treated with telmisartan (TLM), candesartan (CAN), or hydralazine (HYD) and a vehicle group (VEH). Although systolic blood pressure was reduced in the TLM, CAN and HYD groups to the same level, heart rate, SNS activation and oxidative stress in the RVLM were significantly lower in the TLM group only. The pressor effect caused by the microinjection of angiotensin II into the RVLM and the depressor effect caused by the microinjection of tempol, a superoxide dismutase mimetic, into the RVLM were both significantly smaller in TLM, but not in CAN or HYD. These results suggest that orally administered TLM inhibits SNS activation through an anti-oxidant effect via inhibition of AT 1 R in the RVLM of SHRSPs; these results are also independent of depressor effects and are not class effects of ARBs. Keywords: angiotensin II; brain; oxidative stress; sympathetic nervous system INTRODUCTION Sympathetic nervous system (SNS) activation is a main cause of the development and progression of hypertension. 1-4 SNS activation is mainly regulated by the brain, 5-7 and we have demonstrated in rat models with hypertension or heart failure that direct interventions to the brain have beneficial effects because of sympathoinhibition. [8][9][10][11][12][13][14] Particularly in the brain, SNS activation is mainly regulated by the rostral ventrolateral medulla (RVLM) in the brainstem, and the functional integrity of the RVLM is essential for the maintenance of basal vasomotor tone. 5,6 We have demonstrated that oxidative stress in the RVLM produced by the angiotensin II type 1 receptor (AT 1 R) causes SNS activation. 11,14-17 Upregulation of the central AT 1 R is important in the pathophysiology of hypertension. 6,7 Microinjection of AT 1 R blockers (ARBs) into the RVLM or intracerebroventricular infusion of ARBs inhibits SNS activation in hypertensive rats. 15,[18][19][20] However, AT 1 R or oxidative stress in the RVLM have not been targets for the treatment of hypertensive patients because we do not have suitable oral agents to inhibit AT 1 R or oxidative stress in the RVLM of hypertensive patients.

A Systematic Comparison of the Properties of Clinically Used Angiotensin II Type 1 Receptor Antagonists

“…Telmisartan was more effective in inhibiting this central response at lower doses than either losartan or irbesartan (Culman et al, 1999). Orally administered telmisartan also reduced oxidative stress and sympathetic nervous system activation in the rat rostral ventrolateral medulla, whereas candesartan was ineffective in this model (Kishi et al, 2012).…”

Calorie Restriction Improves Cognitive Decline via Up-Regulation of Brain-Derived Neurotrophic Factor

“…20) However, oral administration of telmisartan, an angiotensin II type 1 receptor blocker, protected against cognitive decline via BDNF/TrkB in the hippocampus of hypertensive rats. 21) In that study, the improvement of BDNF/TrkB in the hippocampus was probably due to an antioxidant effect because telmisartan has the potential to reduce oxidative stress in the brain 15,21,28) and BDNF is negatively correlated to oxidative stress. 23) We believe that calorie restriction might increase BDNF via reduction of oxidative stress in the hippocampus of dietary-induced obese and hypertensive rats.…”

Potential Clinical Application of Recently Discovered Brain Mechanisms Involved in Hypertension

“…42,43 Because these effects were not observed for all ARBs, however, it is likely that the effects of various ARBs differ with regard to their sympathoinhibitory and antioxidant effects in the brain. 43 Furthermore, the pressor response evoked by microinjection of angiotensin II is markedly attenuated in SHRSP treated with telmisartan. 43 In addition, the depressor response evoked by tempol or apocynin is attenuated in SHRSP treated with telmisartan.…”

“…Interestingly, telmisartan and olmesartan decreased blood pressure in association with antioxidant effects in the brain. [41][42][43] Despite the fact that baroreflex-mediated sympathoexcitatory responses were observed after hydralazine and diuretic treatments, ARBs did not increase sympathetic activity measured by urinary norepinephrine excretion. 42,43 Because these effects were not observed for all ARBs, however, it is likely that the effects of various ARBs differ with regard to their sympathoinhibitory and antioxidant effects in the brain.…”

“…[41][42][43] Despite the fact that baroreflex-mediated sympathoexcitatory responses were observed after hydralazine and diuretic treatments, ARBs did not increase sympathetic activity measured by urinary norepinephrine excretion. 42,43 Because these effects were not observed for all ARBs, however, it is likely that the effects of various ARBs differ with regard to their sympathoinhibitory and antioxidant effects in the brain. 43 Furthermore, the pressor response evoked by microinjection of angiotensin II is markedly attenuated in SHRSP treated with telmisartan.…”