Intracellular l-arginine concentration does not determine NO production in endothelial cells: Implications on the “l-arginine paradox”

► Our findings provide a possible solution to the “l-arginine paradox”. ► Extracellular l-arginine concentration is the major determinant of NO production. ► Cellular l-arginine action is limited by cellular ARG transport, not the Km of NOS. ► We explain how l-arginine supplementation can work to increase endothelial function.