Angiotensin II AT ₁ Receptor Blockade Reverses Pathological Hypertrophy and Inflammation in Brain Microvessels of Spontaneously Hypertensive Rats

Abstract

Background and Purpose-The spontaneously hypertensive rat (SHR) is vulnerable to brain ischemia and stress and exhibits a chronically stimulated brain angiotensin II system, cerebrovascular hypertrophy, and inflammation. Pretreatment with angiotensin II type 1 (AT 1 ) receptor antagonists protects from brain ischemia and from stress and prevents the development of stress-induced gastric ulcers in part by reducing inflammation in the gastric mucosa. We studied whether AT 1 receptor antagonists could exert antiinflammatory effects in the brain vasculature as a mechanism for their protective effects against ischemia. Methods-Ten-week-old SHR and normotensive Wistar-Kyoto male rats received the AT 1 receptor antagonist candesartan (0.3 mg/kg per day) or vehicle for 28 days via osmotic minipumps. We studied AT 1 receptors, intercellular adhesion molecule-1 (ICAM-1), endothelial nitric oxide synthase (eNOS), and number of macrophages by immunohistochemistry and Western blots. Results-We found increased endothelial AT 1 receptor expression of brain microvessels and middle cerebral artery of SHR. Brain AT 1 receptor inhibition reversed the pathological vascular hypertrophy, increased and normalized eNOS expression, and decreased ICAM-1 expression and the number of adherent and infiltrating macrophages in cerebral vessels of SHR. Conclusions-The antiinflammatory effects of AT 1 receptor antagonists may be an important mechanism in protecting against ischemia.

Angiotensin II AT1 Receptor Blockade Abolishes Brain Microvascular Inflammation and Heat Shock Protein Responses in Hypertensive Rats

“…AT 1 receptor antagonism decreased the expression of NF-kB, TNF-a and IL-1b and eliminated the macrophage infiltration in cerebral microvessels from SHR. Our results support recent findings (Suzuki et al, 2001;Takemori et al, 2000;Ando et al, 2004), indicating that the strong inflammatory response via NF-kB pathway in cerebral microvessels of genetically hypertensive rats is dependent on Ang II stimulation, and can be suppressed by blockade of its AT 1 receptors. Reversal of cerebrovascular inflammation by blockade of the Ang II system could be an important additional mechanism of protection against ischemic brain injury, as is the case in peripheral organs (Hilgers et al, 2001;Dandona et al, 2003).…”

“…In addition, confirming our previous findings (Ando et al, 2004), there were large numbers of infiltrating macrophages from SHR, which were absent in normotensive animals. AT 1 receptor antagonism decreased the expression of NF-kB, TNF-a and IL-1b and eliminated the macrophage infiltration in cerebral microvessels from SHR.…”

“…Immunohistochemistry was performed as described earlier (Ando et al, 2004). Brain sections were treated with the primary antibodies for 60 mins at room temperature.…”

Impact of the AGTR1 A1166C polymorphism on subcortical hyperintensities and cognition in healthy older adults

“…The hemodynamic mechanisms of AngII are primarily mediated through activation of the type 1 angiotensin receptor (AT 1 ; Saavedra 2005) localized to brain regions involved in autonomic function (Ando et al 2004). Increased brain RAS activity is associated with increased AT 1 expression in cerebral arteries and microvessels promoting endothelial dysfunction, vascular inflammation, and blood-brain barrier permeability (Nishimura 2001;Ando et al 2004;Saavedra et al 2006). This AT 1 -induced pathophysiological cascade is characteristic of aging phenotypes causing progressive changes in cerebral circulation and white matter microstructure (Nation et al 2010;Saavedra et al 2011).…”

Aldosterone: good guy or bad guy in cerebrovascular disease?

“…However, ACE inhibition and angiotensin receptor blockade have been found to increase cerebral vessel lumen diameter [8]. Recently, levels of the angiotensin type 1 (AT1) receptor were shown to be increased in the cerebral vasculature of SHR, and AT1 receptor blockade normalized vascular structure [38]. The increase in AT1 receptor levels is of particular interest in light of a recent study by Jaffe and Mendelsohn [39] showing that angiotensin II regulates gene transcription in cultured VSMC.…”