L-arginine supplementation in hypercholesterolemic rabbits normalizes leukocyte adhesion to non-endothelial matrix

L-arginine slows the development of atheromatous lesions, improves endothelium-dependent relaxation, and reduces the vascular superoxide anion production in hypercholesterolemic rabbits. These beneficial effects have been attributed to L-arginine-dependent formation of nitric oxide within the endothelial layer; a direct effect of L-arginine on other cells, however, has not been investigated. We hypothesised that in hypercholesterolemia L-arginine also specifically acts via a direct inhibitory effect on leukocytes, without affecting endothelial cells. The action of L-arginine was compared to vitamin E and the HMG CoA reductase inhibitor lovastatin which are known to attenuate progression of atherosclerosis. Rabbits were fed cholesterol enriched diet and from week five on lovastatin (10 mg/day), vitamin E (300 mg/d) or L-arginine (2% in drinking water) were given. After 16 weeks, blood cholesterol concentration was determined and leukocyte adhesion to cotton wool was measured. In order to exclude any endothelium-mediated effects an adhesion assay to endothelial cells was avoided. Cholesterol-enriched diet increased plasma cholesterol concentration (19+/-3 vs. 1427+/-117 mg/dl). Cholesterol levels were not affected by L-arginine (1344+/-163 mg/dl) or vitamine E (1312+/-243 mg/dl). Lovastatin treatment reduced cholesterol concentration by 35% as compared to the cholesterol group (899+/-51, p<0.05 vs. cholesterol). Cholesterol diet significantly increased leukocyte adhesion to cotton wool (16+/-3% vs 27+/-4%, p<0.05). Lovastatin or vitamine E had no effect on leukocyte adhesion (31+/-4%, 39+/-5), whereas L-arginine completely normalized adhesion (8.8+/-3%).

Rabbits fed high cholesterol diet have increased leukocyte adhesion, which is not affected by lovastatin or vitamine E treatment, but prevented by L-arginine supplementation. A direct inhibitory effect of L-arginine on leukocyte adhesion may contribute to the beneficial effects observed with this substance.