DIETARY L-ARGININE DECREASES MYOINTIMAL CELL-PROLIFERATION AND VASCULAR MONOCYTE ACCUMULATION IN CHOLESTEROL-FED RABBITS

L-arginine, the precursor of endogenous nitric oxide (NO), has been sh own to enhance endothelial function and to reduce the progression of a therosclerosis in cholesterol-fed rabbits. In the present study, we in vestigated whether myointimal cell proliferation is enhanced in hyperc holesterolaemic rabbit aorta and whether chronic treatment of the rabb its with L-arginine or with the NO synthase inhibitor L-NAME influence s this proliferative response and vascular monocyte accumulation. Rabb its were fed 1% cholesterol or normal rabbit chow for 12 weeks. Subgro ups of cholesterol-fed rabbits were treated with oral L-arginine (2.25 %) or L-NAME (3 mg/dl) in drinking water. Myointimal cell proliferatio n was quantified in aortic segments by immunohistochemical detection o f bromodeoxyuridine (BrdU) incorporation into nuclear DNA; vascular mo nocyte accumulation was assessed by immunohistochemistry using a monoc lonal anti-macrophage/monocyte antibody (RAM-11). Plasma levels of L-a rginine and the endogenous NO synthase inhibitor, ADMA, were quantifie d by high-performance liquid chromatography (HPLC). Cholesterol feedin g increased the aortic intima/media (I/M) ratio, which was not measura ble in the control group, to 1.9 +/- 0.3. This was paralleled by enhan ced cell proliferation (cholesterol, 2.4 +/- 0.2%; P < 0.05; control, 0.02 +/- 0.001% BrdU-positive cells per 72 h) and vascular monocyte ac cumulation. Double immunostaining for BrdU and alpha-actin showed that about two thirds of the proliferating cells were smooth muscle cells. ADMA levels increased from 0.8 +/- 0.1 mu mol/l to 2.2 +/- 0.2 mu mol /l in cholesterol-fed rabbits, but were unchanged by L-arginine or L-N AME treatment. Myointimal proliferation and intima/media ratios were c orrelated with ADMA plasma levels. Dietary L-arginine reduced monocyte accumulation by 85 +/- 2% (P < 0.05 vs cholesterol), myointimal cell proliferation (1.8 +/- 0.3% per 72 h; P < 0.05) and intimal thickening (I/M ratio: 0.7 +/- 0.2), whereas the inhibitor of NO synthase, L-NAM E, further increased cell proliferation to 3.1 +/- 0.4% per 72 h (P < 0.05). No significant difference was observed in vascular monocyte inf iltration between the cholesterol and L-NAME groups. We conclude that cell proliferation and vascular monocyte accumulation are enhanced in hypercholesterolaemic rabbit aorta. These atherogenic effects can be a ttenuated by dietary L-arginine. Decreased NO formation might underlie the enhanced monocyte accumulation and cell proliferation in hypercho lesterolaemic rabbit aorta. The observed inhibition of cell proliferat ion adds to our understanding of the antiatherosclerotic effects of L- arginine in vivo. (C) 1998 Elsevier Science Ireland Ltd.