Cyclic AMP elevating agents and nitric oxide modulate angiotensin II‐induced leukocyte‐endothelial cell interactions in vivo

Abstract

1 Angiotensin (Ang-II) is a key molecule in the development of cardiac ischaemic disorders and displays proin¯ammatory activity in vivo. Since intracellular cyclic nucleotides elevating agents have proved to be e ective modulators of leukocyte recruitment, we have evaluated their e ect on Ang-IIinduced leukocyte-endothelial cell interactions in vivo using intravital microscopy within the rat mesenteric microcirculation. 2 Pretreatment with iloprost signi®cantly inhibited (1 nM) Ang-II-induced increase in leukocyte rolling¯ux, adhesion and emigration at 60 min by 96, 92 and 90% respectively, and returned leukocyte rolling velocity to basal levels. Pretreatment with salbutamol or co-superfusion with forskolin exerted similar e ects. 3 When theophylline was administered, leukocyte rolling¯ux, adhesion and emigration elicited by Ang-II were signi®cantly attenuated by 81, 89 and 71% respectively. Rolipram administration caused similar reduction of Ang-II-induced leukocyte responses. 4 Co-superfusion of Ang-II with the NO-donor, spermine-NO, or 8-Br-cyclic GMP, or pretreatment with a transdermal nytroglycerin patch, resulted in a signi®cant reduction of the leukocyte-endothelial cell interactions elicited by Ang-II. 5 Salbutamol preadministration did not modify leukocyte-endothelial cell interactions elicited by either L-NAME or L-NAME+Ang-II, indicating that the inhibitory leukocyte e ects caused by cyclic AMP-elevating agents are mediated through NO release. 6 In conclusion, we have provided evidence that cyclic AMP elevating agents and NO donors, are potent inhibitors of Ang-II-induced leukocyte-endothelial cell interactions. Thus, they could constitute a powerful therapeutical tool in the control of the leukocyte recruitment characteristic of the vascular lesions that occur in cardiovascular disease states where Ang-II plays a critical role.

Mechanisms of Endotoxin Tolerance in Human Intestinal Microvascular Endothelial Cells

“…Several reports have indicated that superoxide radicals increase leukocyte-endothelial cell adhesion, and SOD inhibits increased adhesion mediated by superoxide. In rat mesenteric microvessels, exogenous SOD inhibits leukocyte rolling, adhesion, and emigration induced by angiotensin II (28). In vitro, the adhesion of neutrophils to endothelial cells is increased by hydroxyradicals, and this enhanced PMN adhesion is blocked by SOD/catalase (29).…”

Trans- but Not Cis-Resveratrol Impairs Angiotensin-II–Mediated Vascular Inflammation through Inhibition of NF-κB Activation and Peroxisome Proliferator-Activated Receptor-γ Upregulation

“…Its actions on these enzymes contribute to a reduction in the formation of intracellular reactive oxygen species (ROS). In contrast, Ang-II-induced hypertension is mediated in part by superoxide anion production, whereas free radical generation is also involved in the acute inflammatory response elicited by Ang-II, and t-RESV decreases Ang-II-induced intracellular ROS levels, albeit in vascular smooth muscle cells (32,45,46). ROS generation induces NF-kB activation, and this NF has been shown to activate the transcription of several target genes implicated in the initiation and progression of pathogenesis in atherosclerosis, inflammation, and cancer (44).…”

The recovery of some components of the renin angiotensin system in the rat pancreas after chronic exposure to hypoxic condition

“…Many studies have shown that the RAS may enhance an inflammatory response through the production of inflammatory cytokines (Schieffer et al 2000) and the recruitment of inflammatory cells (Alvarez & Sanz 2001, Kintscher et al 2001. Our recent study showed that experimental pancreatitis was associated with the activation of a local pancreatic RAS .…”