Role of angiotensin II type 1 receptor in the leucocytes and endothelial cells of brain microvessels in the pathogenesis of hypertensive cerebral injury

Publisher Website
Google Scholar
Abstract
To elucidate the mechanisms of activation of polymorphonuclear neutrophils (PMNs) and their adhesion to endothelial cells in hypertensive cerebral injury, and to determine the effects of angiotensin II type 1 (AT1) receptor antagonism on PMNs and endothelial cells. We examined expression of AT1 receptor in PMNs in relation to that in endothelial cells of brain microvessels, using mature stroke-prone spontaneously hypertensive rats (SHRSP). To investigate the expression of AT1 receptor, we used 23-week-old male spSHRs and age-matched Wistar-Kyoto (WKY) rats. For the effects of AT1 receptor blockade, the AT1 receptor antagonist, TCV-116, was orally administered at a dosage of 0.5 mg/kg per day for 4 weeks in rats from age 19 weeks. A PMN-rich fraction was obtained by density gradient using Ficol-hypaque. AT1 receptor expression in PMNs was investigated by immunohistochemistry (avidin-biotinylated peroxidase complex method) and reverse transcriptase-polymerase chain reaction (RT-PCR). Expression of macrophage-1 (Mac-1) in PMNs was examined by flow cytometry. Expression of intercellular adhesion molecule-1, glucose transporter-1 and fibrinogen in the cerebral cortex (occipital region) was investigated by immunohistochemistry. AT1 receptor was identified in PMNs by both immunohistochemistry and RT-PCR. It was also detected in the cerebral cortex. Expression in both types of cells was much more intense in spSHRs than in WKY rats. AT1 receptor antagonism ameliorated the enhanced expression of Mac-1 in PMNs. In addition, it was confirmed that enhanced expression of adhesion molecules and increased permeability of brain microvessels were decreased by AT1 receptor antagonism. The results indicate that both PMNs and brain microvessel endothelial cells possess AT1 receptor, that AT1 receptor antagonism ameliorates endothelial injury via inhibition of PMNs and endothelial cell adhesion, and that angiotensin II must be a key factor in hypertensive endothelial injury.