Oral Intake of Rosiglitazone Promotes a Central Antihypertensive Effect Via Upregulation of Peroxisome Proliferator-Activated Receptor-γ and Alleviation of Oxidative Stress in Rostral Ventrolateral Medulla of Spontaneously Hypertensive Rats

Chan, Samuel H.H.; Kung, Peter S.S.; Chan, Julie Y.H.

doi:10.1161/hypertensionaha.109.149146

Cited by 60 publications

(61 citation statements)

References 57 publications

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“…[37][38][39] In terms of the agonist activity of peroxisome proliferator-activated receptor (PPAR)-g, a previous study suggested that orally administered rosiglitazone, a PPAR-g agonist, promotes a central antihypertensive effect via upregulation of PPAR-g and alleviation of oxidative stress in the RVLM of SHR. 40 Although both TLM and CAN function as partial agonists of PPAR-g, only TLM achieves this effect at therapeutic doses. 41 Further studies are necessary to investigate the differences in central effects elicited by the various ARBs in terms of efficacy, inverse agonist activity and PPAR-g agonist activity.…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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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“…Recently, Chan et al (22) suggested that transcriptional upregulation of mitochondrial uncoupling protein 2 (UCP2) in response to an increase in superoxide plays an active role in the feedback regulation of ROS production in the RVLM (22). Furthermore, oral treatment with rosiglitazone enhances a central antihypertensive effect via an upregulation of peroxisome proliferator-activated receptor-␥ (PPAR-␥) and reduced oxidative stress in the RVLM of SHR (23). Stimulation of PPAR-␥ results in the upregulation of UCP2, thereby reducing oxidative stress.…”

Section: Sources Of Ros Generation In the Brain Stemmentioning

confidence: 99%

Imbalance of central nitric oxide and reactive oxygen species in the regulation of sympathetic activity and neural mechanisms of hypertension

Hirooka

Kishi

Sakai

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

109

108

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Hirooka Y, Kishi T, Sakai K, Takeshita A, Sunagawa K. Imbalance of central nitric oxide and reactive oxygen species in the regulation of sympathetic activity and neural mechanisms of hypertension. Am J Physiol Regul Integr Comp Physiol 300: R818-R826, 2011. First published February 2, 2011 doi:10.1152/ajpregu.00426.2010 and reactive oxygen species (ROS) play important roles in blood pressure regulation via the modulation of the autonomic nervous system, particularly in the central nervous system (CNS). In general, accumulating evidence suggests that NO inhibits, but ROS activates, the sympathetic nervous system. NO and ROS, however, interact with each other. Our consecutive studies and those of others strongly indicate that an imbalance between NO bioavailability and ROS generation in the CNS, including the brain stem, activates the sympathetic nervous system, and this mechanism is involved in the pathogenesis of neurogenic aspects of hypertension. In this review, we focus on the role of NO and ROS in the regulation of the sympathetic nervous system within the brain stem and subsequent cardiovascular control. Multiple mechanisms are proposed, including modulation of neurotransmitter release, inhibition of receptors, and alterations of intracellular signaling pathways. Together, the evidence indicates that an imbalance of NO and ROS in the CNS plays a pivotal role in the pathogenesis of hypertension. blood pressure; sympathetic nervous system; central nervous system; nitric oxide; oxidative stress ACTIVATION OF THE SYMPATHETIC nervous system is critically involved in the pathogenesis of hypertension, from initial occurrence to the development of target organ damage, such as heart failure, stroke, and renal failure (35,36). The importance of the effects of the renin-angiotensin system on the sympathetic nervous system in the pathogenesis of hypertension is recently highlighted (30,31). This is not surprising because both the autonomic nervous system and hormonal factors are the major regulators of blood pressure; therefore, abnormalities of either system are likely to be involved in the pathogenesis of essential hypertension (30,31,37). Esler (30) reported that the sympathetic nervous system is activated in ϳ50% of patients with hypertension, particularly in patients with essential hypertension. Central sympathetic outflow is determined by several important nuclei and their circuits in the central nervous system (CNS) (9, 81). These pathways involve many neurotransmitters and neuromodulators (16,25,38,99). In particular, the brain stem circuitry is now considered crucial for the pathogenesis of hypertension, including both excitatory and inhibitory inputs from the supramedullary nuclei and the baroreceptors (16,25,38,100,115). In this review, we focus on the role of nitric oxide (NO) and reactive oxygen species (ROS) in the brain stem as factors constituting the neural mechanisms of hypertension. Because of the close relationship between NO and ROS, we discuss the individual roles of NO and ROS in the brain stem i...

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“…A third group of animals received microinjection bilaterally into RVLM, nucleus tractus solitarii (NTS), or hypothalamic paraventricular nucleus (PVN) of a lentiviral vector (Lv) carrying small hairpin RNA (shRNA) on week 6 to silence protein inhibitor of neuronal NOS (nNOS; PIN; Lv-PIN shRNA, 1×10 6 pfu/80 nL). The dose of test agents used was adopted from previous studies 12,22,23 or determined in the pilot study. In each experimental group, the levels of fasting plasma glucose, insulin, and triglycerides were determined before, every week, and at the end of 8 weeks of ND or HFD.…”

Section: Methodsmentioning

confidence: 99%

Role of Nitric Oxide Synthase Uncoupling at Rostral Ventrolateral Medulla in Redox-Sensitive Hypertension Associated With Metabolic Syndrome

Chao

Tsay

et al. 2014

Hypertension

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Metabolic syndrome (MetS), which is rapidly becoming prevalent worldwide, is long known to be associated with hypertension and recently with oxidative stress. Of note is that oxidative stress in the rostral ventrolateral medulla (RVLM), where sympathetic premotor neurons reside, contributes to sympathoexcitation and hypertension. This study sought to identify the source of tissue oxidative stress in RVLM and their roles in neural mechanism of hypertension associated with MetS. Adult normotensive rats subjected to a high-fructose diet for 8 weeks developed metabolic traits of MetS, alongside increases in sympathetic vasomotor activity and blood pressure. In RVLM of these MetS rats, the tissue level of reactive oxygen species was increased, nitric oxide (NO) was decreased, and mitochondrial electron transport capacity was reduced. Whereas the protein expression of neuronal NO synthase (nNOS) or protein inhibitor of nNOS was increased, the ratio of nNOS dimer/monomer was significantly decreased. Oral intake of pioglitazone or intracisternal infusion of tempol or coenzyme Q 10 significantly abrogated all those molecular events in high-fructose diet–fed rats and ameliorated sympathoexcitation and hypertension. Gene silencing of protein inhibitor of nNOS mRNA in RVLM using lentivirus carrying small hairpin RNA inhibited protein inhibitor of nNOS expression, increased the ratio of nNOS dimer/monomer, restored NO content, and alleviated oxidative stress in RVLM of high-fructose diet–fed rats, alongside significantly reduced sympathoexcitation and hypertension. These results suggest that redox-sensitive and protein inhibitor of nNOS–mediated nNOS uncoupling is engaged in a vicious cycle that sustains the production of reactive oxygen species in RVLM, resulting in sympathoexcitation and hypertension associated with MetS.

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Oral Intake of Rosiglitazone Promotes a Central Antihypertensive Effect Via Upregulation of Peroxisome Proliferator-Activated Receptor-γ and Alleviation of Oxidative Stress in Rostral Ventrolateral Medulla of Spontaneously Hypertensive Rats

Cited by 60 publications

References 57 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

Imbalance of central nitric oxide and reactive oxygen species in the regulation of sympathetic activity and neural mechanisms of hypertension

Role of Nitric Oxide Synthase Uncoupling at Rostral Ventrolateral Medulla in Redox-Sensitive Hypertension Associated With Metabolic Syndrome

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