ADHESIVENESS OF MONONUCLEAR-CELLS IN HYPERCHOLESTEROLEMIC HUMANS IS NORMALIZED BY DIETARY L-ARGININE

Hypercholesterolemia reduces vascular nitric oxide (NO) activity. This dysfunction may promote endothelial monocyte interaction, as NO is a potent inhibitor of cell adhesion. We have previously shown that in hy percholesterolemic (HC) rabbits, chronic oral supplementation of L-arg inine (Arg) restores NO activity and inhibits monocyte-endothelial cel l interaction, in association with a reduction in atherogenesis, We hy pothesized that enhancement of endothelial NO activity in HC humans wo uld reduce monocyte adhesiveness. We used a functional binding assay t o assess the adhesiveness of human mononuclear cells (MNCs) ex vivo to determine the effects of hypercholesterolemia and L-arginine administ ration. MNCs from HC subjects adhered in greater numbers (50% more cel ls per high-power held; P<.0001) than cells derived from normocholeste rolemic (NC) subjects. To determine whether enhancement of endogenous NO activity could inhibit mononuclear cell adhesiveness, in a double-b linded placebo-controlled study, oral arginine HCl (8.4 g/d) was admin istered to HC subjects. Over a course of 2 weeks, this treatment aboli shed the increased adhesiveness of HC MNCs (160+/-11% versus 104+/-5%; before and after 2 weeks of Arg treatment: results expressed as a per centage of the binding values obtained using cells derived from paired NC individuals). By contrast, MNC adhesion remained significantly ele vated in placebo-treated HC subjects, To examine whether endothelium-d erived NO could act as a paracrine modulator of monocyte behavior, mon ocytes were exposed to NO donors or cocultured in the presence of endo thelial cells exposed to antagonists of NO synthase in the presence or absence of L-arginine. NO donors inhibited monocyte adhesiveness. Fur thermore, the adhesiveness of monocytes cocultured with endothelial ce lls was increased by antagonists of NO synthase, this effect was rever sed by L-arginine. This study shows that the adhesiveness of human MNC s is increased by hypercholesterolemia. The increase in adhesiveness w as reversed in vivo by administration of the NO precursor L-arginine. NO donors or endothelium-derived NO inhibits the adhesiveness of monoc ytes in vitro, supporting the hypothesis that the effects of L-arginin e are mediated by NO.