Blood-brain barrier disruption in the hypothalamus of young adult spontaneously hypertensive rats

Ueno, Masaki; Sakamoto, Haruhiko; Liao, Yingjun; Onodera, Masayuki; Huang, Cheng‐Long; Miyanaka, Hiroshi; Nakagawa, Toshitaka

doi:10.1007/s00418-004-0684-y

Cited by 75 publications

(51 citation statements)

References 47 publications

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“…The surface glycocalyx layer (SGL) of the BBB is located on the luminal surface of the endothelium 43 and contains a great number of solid-bound fixed negative charge. 39,41,45 In addition to the tight junctions in between endothelial cells, the SGL plays an important role in maintaining the barrier function of endothelium due to its matrix-like structure as well as the charge.…”

Section: Introductionmentioning

confidence: 99%

Effect of Surface Charge of Immortalized Mouse Cerebral Endothelial Cell Monolayer on Transport of Charged Solutes

Yuan

2010

Ann Biomed Eng

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Abstract-Charge carried by the surface glycocalyx layer (SGL) of the cerebral endothelium has been shown to significantly modulate the permeability of the blood-brain barrier (BBB) to charged solutes in vivo. The cultured monolayer of bEnd3, an immortalized mouse cerebral endothelial cell line, is becoming a popular in vitro BBB model due to its easy growth and maintenance of many BBB characteristics over repeated passages. To test whether the SGL of bEnd3 monolayer carries similar charge as that in the intact BBB and quantify this charge, which can be characterized by the SGL thickness (L f ) and charge density (C mf ), we measured the solute permeability of bEnd3 monolayer to neutral solutes and to solutes with similar size but opposite charges: negatively charged a-lactalbumin (À11) and positively charged ribonuclease (+3). Combining the measured permeability data with a transport model across the cell monolayer, we predicted the L f and the C mf of bEnd3 monolayer, which is~160 nm and~25 mEq/L, respectively. We also investigated whether orosomucoid, a plasma glycoprotein modulating the charge of the intact BBB, alters the charge of bEnd3 monolayer. We found that 1 mg/mL orosomucoid would increase SGL charge density of bEnd3 monolayer to~2-fold of its control value.

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Section: Introductionmentioning

confidence: 99%

Effect of Surface Charge of Immortalized Mouse Cerebral Endothelial Cell Monolayer on Transport of Charged Solutes

Yuan

2010

Ann Biomed Eng

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“…First, orally administered TLM (2 mg kg À1 per day) could not penetrate the blood-brain barrier, which is not as damaged in WKY rats. In hypertensive rats, the blood-brain barrier is damaged; 43,44 thus, orally administered TLM can easily penetrate the blood-brain barrier of SHRSPs. This possibility would also support our results that orally administered ARB-induced sympathoinhibition through the reduction of oxidative stress via inhibition of the AT 1 R in the RVLM is dependent on the penetration of the blood-brain barrier.…”

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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“…Other mechanisms, such as active transport of the drugs through the blood-brain barrier, should be considered, 9 however, because the hydrophilic AT1-receptor blocker, candesartan, also acts within the brain. 6,9 In addition, blood-brain barrier disruption might occur in SHRSP, 45,46 thereby affecting the effect of olmesartan on the brain. ICV administration of RNH-6270, an active form of olmesartan, reduced SBP, HR and urinary NE excretion in association with the reduced oxidative stress in the brain of SHRSP as assessed by the in vivo ESR technique, suggesting that olmesartan has a direct sympatho-inhibitory and antioxidant action on the brain.…”

Section: Discussionmentioning

confidence: 99%

Olmesartan reduces oxidative stress in the brain of stroke-prone spontaneously hypertensive rats assessed by an in vivo ESR method

et al. 2009

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We previously showed that oxidative stress in the brain is involved in the neural mechanisms of hypertension. Therefore, olmesartan, an angiotensin type 1 receptor blocker, might affect oxidative stress in the brains of stroke-prone spontaneously hypertensive rats (SHRSP). Here, we evaluated the effects of olmesartan treatment using an in vivo electron spin resonance (ESR)/spin probe technique. Two groups of SHRSP were treated with either olmesartan (10 mg kg À1 day À1 ) or hydralazine (Hyd, 20 mg kg À1 day À1 )/hydrochlorothiazide (HCT, 4.5 mg À1 kg day À1 ) for 30 days (n¼5 for each). Systolic blood pressure decreased similarly in both groups after treatment. Heart rate and urinary norepinephrine (NE) excretion increased in rats treated with Hyd/HCT, but not in those treated with olmesartan. The in vivo ESR signal decay rates of the blood-brain barrierpermeable spin probe methoxycarbonyl-PROXYL were significantly higher in SHRSP brains than in age-matched normotensive Wistar-Kyoto rat brains (Po0.01; n¼6 for each). Olmesartan attenuated the ESR signal decay rates in SHRSP brains, but Hyd/HCT did not. Intracerebroventricular infusion of active form of olmesartan, RNH-6270, reduced blood pressure and NE excretion, and the ESR signal decay rate was reduced in SHRSP brains. These findings indicate that olmesartan has anti-oxidative property in the brain without stimulating reflex-mediated sympathetic activity in SHRSP.

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Blood-brain barrier disruption in the hypothalamus of young adult spontaneously hypertensive rats

Cited by 75 publications

References 47 publications

Effect of Surface Charge of Immortalized Mouse Cerebral Endothelial Cell Monolayer on Transport of Charged Solutes

Effect of Surface Charge of Immortalized Mouse Cerebral Endothelial Cell Monolayer on Transport of Charged Solutes

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

Olmesartan reduces oxidative stress in the brain of stroke-prone spontaneously hypertensive rats assessed by an in vivo ESR method

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