Angiotensin II induces leukocyte-endothelial cell interactions in vivo viaAT(1) and AT(2) receptor-mediated P-selectin upregulation

Background-Angiotensin II (Ang II) plays a critical role in the development of vascular lesions in hypertension, atherosclerosis, and several renal di seases. Because Ang II may contribute to the leukocyte recruitment associat ed with these pathological states, the aim of the present study was to asse ss the role of Ang II in leukocyte-endothelial cell interactions in vivo. Methods and Results-Intravital microscopy of the rat mesenteric postcapilla ry venules was used. Sixty minutes of superfusion with 1 nmol/L Ang II indu ced a significant increase in leukocyte rolling flux (83.8+/-20.7 versus 16 .4+/-3.1 cells/min), adhesion (11.4+/-1.0 versus 0.8+/-0.5 cells/100 mum), and emigration (4.0+/-0.7 versus 0.2+/-0.2 cells/field) without any vasocon strictor activity. These effects were not mediated by mast cell activation. Intravenous pretreatment with AT(1) (losartan) or AT(2) (PD123,319) recept or antagonists significantly reduced Ang II-induced responses. A combinatio n of both receptor antagonists inhibited the leukocyte rolling flux, adhesi on, and extravasation elicited by Ang II at 60 minutes. Pretreatment of ani mals with fucoidin or an adhesion-blocking anti-rat P-selectin monoclonal a ntibody abolished Ang II-induced leukocyte responses. Furthermore, rat plat elet P-selectin expression was not affected by Ang II stimulation. Conclusions-Ang II. induces significant leukocyte rolling, adhesion, and em igration, which may contribute not only to hypertension but also to the ons et and progression of the vascular damage associated with disease states in which plasma levels of this peptide are elevated.