Angiotensin II mediates postischemic leukocyte-endothelial interactions: role of calcitonin gene-related peptide

Department of Medical Pharmacology and Physiology and Dalton Cardiovascular Research Center, University of Missouri-Columbia School of Medicine, Columbia, Missouri Submitted 2 November 2006 ; accepted in final form 12 February 2007 Vascular inflammation and enhanced production of angiotensin II (ANG II) are involved in the pathogenesis of hypertension and diabetes, disease states that predispose the afflicted individuals to ischemic disorders. In light of these observations, we postulated that ANG II may play a role in promoting leukocyte rolling (LR) and adhesion (LA) in postcapillary venules after exposure of the small intestine to ischemia-reperfusion (I/R). Using an intravital microscopic approach in C57BL/6J mice, we showed that ANG II type I (AT 1 ) or type II (AT 2 ) receptor antagonism (with valsartan or PD-123319, respectively), inhibition of angiotensin-converting enzyme (ACE) with captopril, or calcitonin gene-related peptide (CGRP) receptor blockade (CGRP8-37) prevented postischemic LR but did not influence I/R-induced LA. However, both postischemic LR and LA were largely abolished by concomitant AT 1 and AT 2 receptor blockade or chymase inhibition (with Y-40079). Additionally, exogenously administered ANG II increased LR and LA, effects that were attenuated by pretreatment with a CGRP receptor antagonist or an NADPH oxidase inhibitor (apocynin). Our work suggests that ANG II, formed by the enzymatic activity of ACE and chymase, plays an important role in inducing postischemic LR and LA, effects that involve the engagement of both AT 1 and AT 2 receptors and may be mediated by CGRP and NADPH oxidase. ischemia; reperfusion; leukocyte rolling; leukocyte adhesion; angiotensin-converting enzyme; chymase; angiotensin AT 1 and AT 2 receptors; NADPH oxidase Address for reprint requests and other correspondence: R. J. Korthuis, Dept. of Medical Pharmacology and Physiology, Univ. of Missouri-Columbia School of Medicine, One Hospital Dr., Columbia, MO 65212 (e-mail: korthuisr{at}health.missouri.edu )