NITRIC OXIDE-GENERATING SYSTEM AS AN AUTOCRINE MECHANISM IN HUMAN POLYMORPHONUCLEAR LEUKOCYTES

Recent data [Lopez-Farre, Riesco, Moliz, Egido, Casado, Hernando and C aramelo (1991) Biochem. Biophys. Res. Commun. 178, 884-891] revealed t hat endothelin 1 (ET-1) increases intracellular free [Ca2+] in polymor phonuclear leucocytes (PMN) by a mechanism that can be inhibited by L- arginine. The aim of the present study was to clarify the mechanisms o f the interaction between the effects of ET-1 and L-arginine in human PMN. The experimental findings showed that in human PMN: (a) ET-1 and the chemoattractant peptide N-formylmethionyl-leucyl-phenylalanine (fM LP) induce both the metaboliSM of L-arginine to L-citrulline and cycli c GMP (cGMP) formation; (b) the ET-1-induced cGMP production is inhibi table by the L-arginine antagonist N(G)-monomethyl-L-arginine, therefo re suggesting the involvement of NO; (c) the ET-1- or fMLP-induced NO/ cGMP stimulation is critically dependent on the availability Of L-argi nine; (d) human PMN possess a L-arginine transport system with both Na +-dependent and -independent components; (e) the L-arginine transport system in PMN appears to be feedback-regulated by NO/cGMP in ET-1-stim ulated conditions, but not under baseline conditions; (f) the L-argini ne transport system in PMN is independent of the gamma-glutamyl cycle and is not modified by either ET-1 or fMLP. The L-arginine/NO/cGMP-dep endent mechanisms characterized in the present study may be relevant i n the regulation of PMN activation in pathophysiological conditions in vivo.