Atrial natriuretic factor modulates nitric oxide production: an ANF-C receptor-mediated effect

Abstract

Objectives: To investigate the possible immunomodulatory and regulatory functions of atrial natriuretic factor (ANF) and the natriuretic peptide C (NPR-C) receptor in the control of cytokine-stimulated nitric oxide production in primary cultures of human proximal tubular cells. Methods: Freshly prepared human proximal tubular cells were seeded on plastic plates and allowed to reach confluence. The confluent cells were 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 nitric oxide-stimulating combination of cytokines interleukin-1|3 (10u/ml), tumour necrosis factor-cc (10ng/ml) and interferon-y (100 u/ml). Results: In the present series of experiments we have found that incubation of primary cultures of human proximal tubular cells with ANF or C(4_23)ANF stimulates nitric oxide production dose-dependently. Paradoxically, ANF acting via the NPR-C receptor also inhibits cytokine activation of the enzyme-inducible nitric oxide synthase via a cyclic GMP-independent mechanism. Both of these effects were reproduced by the NPR-C receptor-specific ligand cIn the present series of experiments we have found that incubatio4_23)ANF. Conclusions: These findings represent novel actions of ANF mediated via the NPR-C receptor. The results also provide a simple model system in which to study the subcellular mechanisms of NPR-C receptor activation.