EFFECT OF ATRIAL-NATRIURETIC-PEPTIDE AND CYCLIC-GMP PHOSPHODIESTERASEINHIBITION ON COLLAGEN-SYNTHESIS BY ADULT CARDIAC FIBROBLASTS

1 Cardiac fibroblasts play an important role in the pathophysiology of cardiac remodelling induced by hypertension and myocardial infarction by undergoing proliferation and depositing extracellular matrix prote ins such as collagen. We have examined the effects of atrial natriuret ic peptide (ANP) on proliferation and collagen synthesis by adult rat and human cardiac fibroblasts in culture. 2 In cells from both species radioligand studies using I-125-ANP suggested that the majority of bi nding sites (>85%) were non-guanylyl cyclase-linked (NPR-C subtype). N onetheless ANP (10(-9) to 10(-6) M), in the presence of zaprinast, an inhibitor of phosphodiesterase 5 (PDE5), increased fibroblast cyclic G MP levels 3 - 5 fold in a concentration-dependent manner (P < 0.0 5). 3 ANP (10(-11) to 10(-6) M), a NPR-C ligand, C-ANF4-23 (10(-11) to 10( -6) M) and zaprinast alone had no significant effect on either basal o r serum-stimulated DNA synthesis or fibroblast number. In combination with zaprinast (10(-5) M), however, ANP (10(-9) to 10(-6) M) but not C -ANF4-23 (10(-7) M) inhibited markedly both basal and stimulated fibro blast mitogenesis, an effect reproduced by 8-bromocyclic GMP (10(-5) t o 10(-3) M). 4 Collagen synthesis, determined by measuring hydroxyprol ine levels, was stimulated with transforming growth factor-beta 1 (40 pM), angiotensin II (10(-7) M) or 2% foetal bovine serum. The increase in collagen production, normalised by cell number, was reduced dramat ically (to at or near basal production) by ANP (10(-9) to 10(-7) M) bu t not C-ANF4-23 (10(-7) M) in the presence of zaprinast. Again 8-bromo -cyclic GMP (10(-5) to 10(-3) M) reproduced the effect. 5 ANP is capab le of inhibiting collagen synthesis in adult rat and human cardiac fib roblasts via cyclic GMP, a property unmasked and enhanced by inhibitio n of PDE5.