Amlodipine-Induced Reduction of Oxidative Stress in the Brain Is Associated with Sympatho-Inhibitory Effects in Stroke-Prone Spontaneously Hypertensive Rats

Hirooka, Yoshitaka; Kimura, Yoshikuni; Nozoe, Masafumi; Sagara, Yoji; Izutsu, Koji; Sunagawa, Kenji

doi:10.1291/hypres.29.49

Cited by 47 publications

(32 citation statements)

References 63 publications

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“…29 We also previously demonstrated that orally administered atorvastatin, azelnidipine or amlodipine also causes sympathoinhibition through the reduction of oxidative stress in the RVLM of SHRSPs. [45][46][47] However, the results of the present study could not directly elucidate the clinical benefits of TLM in hypertensive patients because the dose of TLM in the present study is not a clinical dose, and there are no clinical trials demonstrating the same reduction in heart rate obtained in the present study. Furthermore, damage to the blood-brain barrier may be much more significant in SHRSPs than in hypertensive human patients.…”

Section: Discussionmentioning

confidence: 59%

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

2012

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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.

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Section: Discussionmentioning

confidence: 59%

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

2012

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“…These observations together with our results suggest the genetic influence of the chr-1 QTL on RSNA. Recent reports have indicated that the augmented superoxide production in the brain stem might be responsible for the activation of the SNS and contribute to the elevation of BP in SHRSP (27)(28)(29). It would be of interest to measure the oxidative stress and the NADPH oxidase activity in the brain stem of the reciprocal congenic strains studied in the present report.…”

Section: Discussionmentioning

confidence: 92%

Sympathetic Regulation of the Renal Functions in Rats Reciprocally Congenic for Chromosome 1 Blood Pressure Quantitative Trait Locus

et al. 2008

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“…31,32 Azelnidipine has been shown to decrease sympathetic nerve activity in the rostral ventrolateral medulla via its antioxidant effect. 10 Hirooka et al 33 reported that amlodipine also decreases the generation of reactive oxygen species in several areas of the brain and decreases sympathetic nerve activity in stroke-prone, spontaneously hypertensive rats. However, another report suggested that amlodipine treatment increases sympathetic nerve activity.…”

Section: Discussionmentioning

confidence: 99%

Azelnidipine attenuates glomerular damage in Dahl salt-sensitive rats by suppressing sympathetic nerve activity

et al. 2011

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Dihydropyridine-type calcium channel blockers (CCBs) exert potent antihypertensive effects. The CCB azelnidipine decreases heart rate by suppressing sympathetic nerve activity, which affects afferent and efferent arterioles in the glomeruli. We examined whether azelnidipine can improve progressive glomerular injury in comparison with amlodipine by suppressing renal sympathetic nerve activity in Dahl salt-sensitive rats. Glomerular circulation in Dahl salt-sensitive rats was monitored with a charge-coupled device camera before and after administration of amlodipine (0.5 mg kg À1 , bolus injection) or azelnidipine (0.1 mg kg À1 , bolus injection). Systemic sympathetic nerve activity was also compared by analysis of heart rate variability with a telemetry blood pressure monitoring system after crossover administration of amlodipine (1.0 mg kg À1 per day) and azelnidipine (3.0 mg kg À1 per day) for 1 week. To investigate renoprotective effects, rats were treated with amlodipine (1.0 mg kg À1 per day) or azelnidipine (3.0 mg kg À1 per day) for 3 weeks with or without renal denervation. The efferent arteriole contracted in response to acute amlodipine but not azelnidipine treatment. The low frequency/high frequency ratio, an index of parasympathetic nerve activity, decreased in response to azelnidipine but not amlodipine treatment. In response to chronic treatment, proteinuria and glomerular injury improved to a greater extent with azelnidipine compared with amlodipine. The renoprotective effects of azelnidipine were diminished by renal denervation. Azelnidipine decreased glomerular damage in Dahl salt-sensitive rats to a greater extent than amlodipine. Azelnidipine appeared to decrease intraglomerular pressure by suppressing sympathetic nerve activity.

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Amlodipine-Induced Reduction of Oxidative Stress in the Brain Is Associated with Sympatho-Inhibitory Effects in Stroke-Prone Spontaneously Hypertensive Rats

Cited by 47 publications

References 63 publications

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

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

Sympathetic Regulation of the Renal Functions in Rats Reciprocally Congenic for Chromosome 1 Blood Pressure Quantitative Trait Locus

Azelnidipine attenuates glomerular damage in Dahl salt-sensitive rats by suppressing sympathetic nerve activity

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