ATRIAL-NATRIURETIC-FACTOR MODULATES NITRIC-OXIDE PRODUCTION - AN ANF-C RECEPTOR-MEDIATED EFFECT

Objectives: To investigate the possible immunomodulatory and regulator y functions of atrial natriuretic factor (ANF) and the natriuretic pep tide C (NPR-C) receptor in the control of cytokine-stimulated nitric o xide production in primary cultures of human proximal tubular cells. M ethods: Freshly prepared human proximal tubular cells were seeded on p lastic plates and allowed to reach confluence. The confluent cells wer e then incubated with ANF or cyclic((4-23))ANF (C-(4-23)ANF) alone, or preincubated with ANF or C-(4-23)ANF before incubation with the nitri c oxide-stimulating combination of cytokines interleukin-1 beta (10 u/ ml), tumour necrosis factor-alpha (10 ng/ml) and interferon-gamma (100 u/ml). Results: In the present series of experiments we have found th at incubation of primary cultures of human proximal tubular cells with ANF or C-(4-23)ANF stimulates nitric oxide production dose-dependentl y, Paradoxically, ANF acting via the NPR-C receptor also inhibits cyto kine activation of the enzyme-inducible nitric oxide synthase via a cy clic GMP-independent mechanism. Both of these effects were reproduced by the NPR-C receptor-specific ligand C-(4-23)ANF. Conclusions: These findings represent novel actions of ANF mediated via the NPR-C recepto r. The results also provide a simple model system in which to study th e subcellular mechanisms of NPR-C receptor activation.