Local l -Arginine Delivery After Balloon Angioplasty Reduces Monocyte Binding and Induces Apoptosis

Abstract

Background-Local administration of L-arginine after balloon angioplasty has been shown to enhance NO generation and inhibit lesion formation. In this study, we assessed the mechanisms by which local delivery of L-arginine inhibits lesion formation. Methods and Results-New Zealand White rabbits (nϭ56) were fed a 1% cholesterol diet. After 1 week, both iliac arteries were balloon-denuded, and a local drug delivery catheter was introduced into both iliac arteries to deliver either L-arginine (800 mg/5 mL with and without 100 Ci L-[2,3-3 H]-arginine) or saline. Monocyte-endothelial interaction was assessed by functional binding assay; NO activity was measured by chemiluminescence. Intramural administration of radioactively labeled L-arginine led to significantly higher counts in comparison to the contralateral segment for up to 1 week after delivery (676Ϯ223 versus 453Ϯ93 cpm/mg; PϽ0.02); this was associated with significantly higher NO levels in the L-arginine-treated segments (394.4Ϯ141.6 versus 86.3Ϯ34.3 nmol/mg; PϽ0.01). Even after 2 to 3 weeks, monocyte binding was significantly decreased by treatment with L-arginine as compared with saline infusion (PϽ0.01). After 4 weeks, there was a 9-fold greater number of apoptotic cells in the vessel wall of L-arginine as compared with the saline-treated segments (PϽ0.05). Conclusions-Intramural delivery of L-arginine immediately after angioplasty causes a sustained increase in tissue L-arginine levels associated with enhancement of local NO synthesis. The local increase in NO synthesis is associated with an attenuation of monocyte binding and increased apoptosis of resident macrophages. This treatment strategy could be valuable for the prevention and management of restenosis.

Effects of nitric oxide-releasing aspirin versus aspirin on restenosis in hypercholesterolemic mice

“…This phenomenon was similar to that observed by Niebauer et al (13) when using local L-arginine delivery in an experimental model of restenosis. The therapeutic response to L-arginine may have been attributed to endogenous NO as L-arginine is converted to NO in vascular endothelial cells.…”

“…There is evidence that modulation of NO-dependent pathways may be used to modify the development of restenosis. For example, the administration of L-arginine, the precursor to NO, reduces restenotic lesion formation and monocyte recruitment in cholesterol-fed rabbits (12,13), whereas L-NAME, a nonselective inhibitor of NO-synthase, stimulates neointimal hyperplasia (14). Thus, increased NO production at the site of balloon injury may exert beneficial effects.…”

Nitric oxide: a key regulator of myeloid inflammatory cell apoptosis

“…How the results obtained in these systems relate to the in vivo situation during inflammation in humans still largely remains to be determined, but two studies in rabbits show that NO is a promising candidate for treatment or prevention of inflammatory conditions such as atherosclerosis and restenosis, possibly by influencing apoptosis. 74,75 Further studies are required to elucidate completely the mechanism of action of NO on inflammatory cell apoptosis, in order to identify potential targets for the treatment of human inflammatory conditions and to evaluate the sources of NO that provide greatest therapeutic potential.…”

“…Studies have suggested that lower doses of NO may be detrimental but that higher doses may attenuate the inflammatory response, with some authors proposing a role for the cytotoxic effects of NO on myeloid inflammatory cells. 69,[73][74][75] NO appears to be particularly effective in autoimmune conditions, such as experimental allergic encephalomyelitis (EAE), which serves as a model for human multiple sclerosis. 76 In this model, several studies have reported that iNOS-deficient rats or mice that were immunised directly with myelin basic protein developed exacerbated disease, although results obtained following immunisation with myelin basic protein-specific T cells often contradict these findings.…”

“…80 Two in vivo studies were published in 1999, investigating the effects of NO on macrophage apoptosis in cardiovascular disease of cholesterol-fed rabbits. Niebauer et al 75 demonstrated that provision of L-arginine (the substrate for NOS) in drinking water could reduce the formation of inflammatory lesions following balloon angioplasty, while Wang et al 74 showed that it decreased existing atherosclerotic lesions, by inducing macrophage apoptosis.…”