Continuous Perivascularl-Arginine Delivery Increases Total Vessel Area and Reduces Neointimal Thickening After Experimental Balloon Dilatation

Abstract

The aim of this study was to evaluate whether vascular remodeling and neointimal thickening occur after balloon dilatation of the nonatherosclerotic rabbit carotid artery, and whether both processes are influenced by continuous perivascular delivery of L-arginine or the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME). In the first experiment, histological and morphometric evaluation of arteries was performed at different time points after balloon dilatation: 10 minutes (n=7), and 1 (n=7), 2 (n=9), 3 (n=20), or 10 (n=5) weeks. Neointimal thickening progressively contributed to luminal narrowing for at least 10 weeks after angioplasty. During the first 2 weeks after dilatation, a significant decrease of the total vessel area was measured. Ten weeks after dilatation, both the neointimal and total vessel area were increased without further changing of the luminal area. In the second experiment, endothelial injured rabbits were randomly assigned to receive 2 weeks of continuous local perivascular physiological salt solution (n=6), L-arginine (n=8), or L-NAME (n=7), starting immediately after balloon dilatation (ie, local drug delivery during the first phase of the biphasic vascular remodeling process). Perivascular L-arginine delivery significantly reduced the neointimal area, despite an increased number of neointimal Ki-67-positive smooth muscle cells. Both the luminal area and total vessel area were significantly increased. Serum L-arginine levels remained unchanged. L-NAME administration had no effect on the neointimal area, nor on the luminal and total vessel area. Neointimal formation and biphasic vascular remodeling occur after experimental balloon dilatation of the nonatherosclerotic rabbit carotid artery, and can be influenced by continuous local perivascular delivery of L-arginine.

Endothelial NO Synthase Overexpression Inhibits Lesion Formation in Mouse Model of Vascular Remodeling

“…A number of studies using experimental balloon angioplasty demonstrated the protective role of NO derived from eNOS on vascular remodeling characterized by neointimal formation with the use of eNOS gene transfer or the administration of L-arginine, a substrate for NO. [7][8][9]16,17 However, in the balloon angioplasty-induced vascular remodeling model, the endothelium is injured, and the role of NO produced from the endothelium cannot be fully elucidated. Therefore, the use of the vascular remodeling model in which the endothelium remains intact during the lesion formation process would be required to elucidate directly the role of NO from the endothelium on remodeling.…”

Failure of <i>L</i>-Nitroarginine to Inhibit the Activity of Aortic Inducible Nitric Oxide Synthase

“…Failure to block inducible NO synthase has been shown in other reports [13, 14]. The extent to which L-NAME or L-NA inhibit inducible NO synthase is of crucial importance because this isoform is expressed in many pathophysiological conditions [15].…”

Improvement of ventricular function in systolic heart failure patients with oral L-citrulline supplementation

“…Perivascular delivery of L-arginine reduced vascular remodeling and neointimal thickening after balloon dilatation of rabbit coronary artery [27]. In addition, intravenous infusion of L-arginine enhanced cardiac performance in patients with severe congestive HF, mainly by affecting systemic vascular resistance [28] increasing maximum vasodilatation during reactive hyperemia and reducing peripheral resistance in patients with HF [29,30].…”