Role of angiotensin II in ischemia/reperfusion‐induced leukocyte‐endothelium interactions in the colon

Abstract

The aims of the present study were to determine the effects and mechanisms of angiotensin II (Ang II) on leukocyte-endothelium interactions and the role of Ang II in a novel model of ischemia/reperfusion (I/R) in the mouse colon. Ang II dose-dependently increased leukocyte rolling and adhesion in colonic venules. Importantly, Ang II-induced leukocyte rolling was completely inhibited by immunoneutralization of P-selectin, and leukocyte adhesion was abolished in lymphocyte function antigen-1 (LFA-1)-deficient mice. The P-selectin-dependent rolling was found to be a precondition for the subsequent LFA-1-dependent leukocyte adhesion. Moreover, Ang II-induced leukocyte responses involved generation of reactive oxygen species and up-regulation of CXC chemokines. Notably, CXC chemokines, but not Ang II, stimulated leukocyte chemotaxis in vitro. I/R increased gene expression of angiotensin converting enzyme (ACE) in the colon and plasma concentrations of Ang II. Inhibition of ACE and the type 1 angiotensin (AT1) receptor significantly decreased the I/R-induced leukocyte adhesion. Taken together, these novel findings demonstrate that Ang II exerts potent pro-inflammatory effects in the colonic microcirculation and that inhibition of Ang II expression or function protects against I/R-induced leukocyte responses in the colon. Thus, it is suggested that Ang II is a major target to control pathological inflammation in the colon.

Evaluation of Effects of Losartan on Random Pattern Skin Flap Model of Rats

“…[12,14] Activation of these receptors causes an increase in inflammatory response. [12,[16][17][18][19] Losartan, which is an angiotensin type 1 (AT1) receptor blocker, has antiinflammatory properties via acting on local systems. Zhu and Sato et al showed this drug's ability to reduce the area of infarction in the myocardium.…”

“…[20,21] Moreover, losartan prevents ischemia-reperfusion injury in many organs including the heart, [16,22] liver, [12] lungs, [23] endothelium, [24] brain, [25] and large intestine. [19] We hypothesize that ischemic damage in the skin may also be decreased if proinflammatory properties of angiotensin were inhibited. In this study, the effects of losartan on ischemic skin flaps and its possible role in improving flap survival were investigated.…”

“…[2,3,6,10,16] Inhibition of neutrophil functions has been shown to improve flap survival. [2,4,6,10] We hypothesized that AT1 blockers may improve flap survival by inhibiting adhesion of neutrophils to the endothelium, [16,17,19] decreasing tumor necrosis factor (TNF) alpha and interleukin (IL)-8 levels, [12,15] modifying nitric oxide production, [16] inhibiting platelet aggregation, [30,31] and preventing apoptosis. [21,24,25] Despite our expectations, comparison of flap survivals did not yield any differences between the study groups.…”

“…Previous studies that showed losartan's ability to reduce ischemic damage were done on organ models such as the myocardium, [16,22] endothelium, [24] liver, [12] brain, [25] and large intestine. [19] Although AT1 receptors are present on rat skin, [32,33] the literature is devoid of any studies about losartan's effect on these receptors. Also, the studies mentioned above were done on ischemia-reperfusion models.…”

“…Losartan has well-known inhibitor actions on neutrophils in various organs such as the heart, [16] liver, [12] mesenteric venules, [17] large intestine, [19] and stomach. [15] The drug acts via suppression of neutrophil functions (rolling, adhesion, migration) and causes an eventual decrease in extravascular infiltration.…”