Intra-carotid angiotensin II activates tyrosine hydroxylase-expressing rostral ventrolateral medulla neurons following blood–brain barrier disruption in rats

Abstract

Angiotensin II (Ang II) in the periphery and within the brain plays important roles in blood pressure control. Circulating angiotensin is normally excluded from the brain by the blood-brain barrier (BBB), but there is evidence that in some diseases there is disruption of the BBB that could allow circulating Ang II to access nuclei from which it is normally excluded, such as the rostral ventrolateral medulla (RVLM). We therefore investigated whether disruption of the BBB leads to increased activation by circulating Ang II of tyrosine hydroxylase (TH)-containing neurons in the RVLM. In anaesthetised rats, in which the BBB was disrupted with intracarotid hypertonic mannitol (1.6M, 2mL/kg), subsequent intracarotid infusion of a subpressor dose of Ang II (5ng/kg) activated ∼24% of TH-containing RVLM neurons whereas saline only activated ∼8% of TH neurons. Intracarotid pretreatment with the Ang II receptor type 1 (AT1R) blocker, losartan (20μg/kg), significantly reduced the number of TH cells activated to ∼11% (P<0.05, one-way analysis of variance, n=5). In summary, disruption of the BBB resulted in increased activation by circulating Ang II of TH-containing cells in the RVLM. The activation was reduced by losartan indicating a specific action on AT1Rs. These results suggest that disruption of the BBB allows entry of circulating Ang II into the RVLM, which could increase sympathetic outflow. This potential source of Ang II within the RVLM might be an important consideration when assessing sympathetic nerve activity in disease states associated with a compromised BBB.

Circulating Angiotensin II Gains Access to the Hypothalamus and Brain Stem During Hypertension via Breakdown of the Blood–Brain Barrier

“…Since AngII stimulates the activity of PVN 60,61 , RVLM 62 and NTS 63 neurons, binding of circulating, extravasated AngII to these neurons may directly contribute to sympathetic outflow and elevated BP during hypertension. This is also supported by a recent study showing an AT1r-mediated activation of bulbospinal, tyrosine hydroxylase RVLM neurons following a hypertonic-induced disruption of the BBB 24 .…”

“…Whereas we found minimal FITC10 extravasation in the PVN and SON (areas with an intact BBB, Fig.S1-C, D), large amounts were found in the SFO and the area postrema (Fig.S1-A, B), which lack a complete BBB. Furthermore, intracarotid infusion of a hypertonic solution known to disrupt the BBB 22–24 , resulted in FITC10 extravasation in the PVN of control rats (8.1±0.6 % area, n=6), which appeared as punctate aggregates throughout the parenchyma (Figs.S1,S2 and Figs.2,3), as well as diffuse staining within perivascular cells surrounding capillaries (putative pericytes) (Fig.S2-B). …”

“…When indicated, hypertonic mannitol (1.4M, 2ml per 200–250g of animal; Sigma-aldrich, MO) 22–24 was infused intracarotidly 5 min prior to the dextrans. Hypothalamic and brainstem sections (40µm) were counterstained (Toto 1:50000).…”

A Salt-Induced Reno-Cerebral Reflex Activates Renin-Angiotensin Systems and Promotes CKD Progression

“…36 The number of c-fos-positive and TH-expressing neurons in the RVLM was determined as previously described. 71 Briefly, brain stem sections were double stained with antibodies against TH (EMD Millipore) and c-fos (Santa Cruz Biotechnology) and the number of labeled TH and c-fos immunopositive neurons located within the defined borders of the RVLM was assessed as delineated in the atlas of Paxinos and Watson.…”

A disfunção da barreira hematoencefálica em SHR é normalizada pelo treinamento aeróbio de baixa a moderada intensidade.

“…A eficácia do treinamento aeróbio realizado pôde ser aferida por sua capacidade em induzir em ambos os grupos bradicardia de repouso, um importante marcador de treinabilidade (CLAUSEN, 1977 (BRAGA et al, 2000;CHAAR et al, 2015;DE ANGELIS, et al, 2004;MASSON et al, 2014;VÉRAS-SILVA et al, 1997 (CHAAR et al, 2015;GOMÉZ-ANGELATS et al, 2004;HÖCHT, 2013;LEONCINI et al, 2013;MASSON et al, 2014;SU;MIAO, 2011;TATASCIORE et al, 2007). Importante foi nossa observação (JAPUNDZIC et al, 1990;PARATI et al, 1995;STAUSS, 2007 BIANCARDI et al, 2014;CAPONE et al, 2011;SMEDA, 2010;IADECOLA, 2013;FLEEGAL-DE-MOTTA et al, 2009;DAVISSON, 2008;MUELLER;TANG et al, 1993;UENO et al, 2004;YAO;MAY, 2013;ZHANG et al, 2010). Com exceção do trabalho recente de Biancardi et al, (2014) (BRAGA et al, 2000;CAVALLERI et.…”