CHLOROQUINE STIMULATES NITRIC-OXIDE SYNTHESIS IN MURINE, PORCINE, ANDHUMAN ENDOTHELIAL-CELLS

Nitric oxide (NO) is a free radical involved in the regulation of many cell functions and in the expression of several diseases. We have fou nd that the antimalarial and antiinflammatory drug, chloroquine, is ab le to stimulate NO synthase (NOS) activity in murine, porcine, and hum an endothelial cells in vitro: the increase of enzyme activity is depe ndent on a de novo synthesis of some regulatory protein, as it is inhi bited by cycloheximide but is not accompanied by an increased expressi on of inducible or constitutive NOS isoforms. Increased NO synthesis i s, at least partly, responsible for chloroquine-induced inhibition of cell proliferation: indeed, NOS inhibitors revert the drug-evoked bloc kage of mitogenesis and ornithine decarboxylase activity in murine and porcine endothelial cells. The NOS-activating effect of chloroquine i s dependent on its weak base properties, as it is exerted also by ammo nium chloride, another lysosomotropic agent. Both compounds activate N OS by limiting the availability of iron: their stimulating effects on NO synthesis and inhibiting action on cell proliferation are reverted by iron supplementation with ferric nitrilotriacetate, and are mimicke d by incubation with desferrioxamine, Our results suggest that NO synt hesis can be stimulated in endothelial cells by chloroquine via an imp airment of iron metabolism.