Angiotensin II mediates postischemic leukocyte-endothelial interactions: role of calcitonin gene-related peptide.
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.
Yusof
Mozow
M
Department of Medical Pharmacology and Physiology, Dalton Cardiovascular Research Center, University of Missouri-Columbia School of Medicine, One Hospital Dr., Columbia, MO 65212, USA.
Kamada
Kazuhiro
K
Gaskin
F Spencer
FS
Korthuis
Ronald J
RJ
D000098:Acetophenones / Q000494:pharmacology; D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D057912:Angiotensin II Type 2 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism*; D002216:Captopril / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D053818:Chymases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D007422:Intestines / Q000098:blood supply*; D007511:Ischemia / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D036904:Leukocyte Rolling / Q000187:drug effects; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018715:Microscopy, Video; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000378:metabolism; D015427:Reperfusion Injury / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D013777:Tetrazoles / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan; D014699:Venules / Q000378:metabolism
D000098:Acetophenones; D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D011744:Pyrimidinones; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D018015:Receptors, Calcitonin Gene-Related Peptide; D013777:Tetrazoles; C424917:Y 40079; D000804:Angiotensin II; C073402:PD 123319; D000068756:Valsartan; D002216:Captopril; C056165:acetovanillone; D019255:NADPH Oxidases; D053818:Chymases; D014633:Valine; D015740:Calcitonin Gene-Related Peptide