Nitric oxide-generating vasodilators inhibit mitogenesis and proliferation of BALB/C 3T3 fibroblasts by a cyclic GMP-independent mechanism

Abstract

The purpose of this study was to investigate the effects of nitric oxide-generating vasodilators and 8-bromo-cGMP on serum-induced mitogenesis in BALB/c 3T3 fibroblasts that lack soluble guanylate cyclase activity. Two such vasodilators, S-nitroso-N-acetylpenicillamine and isosorbide dinitrate, decreased the incorporation of (3H)thymidine in these cells dose-dependently whereas 8-bromo-cGMP was ineffective at concentrations of up to 10 mM. Moreover, S-nitroso-N-acetylpenicillamine also inhibited cell proliferation, consistent with the data on (3H)thymidine incorporation. S-nitroso-N-acetylpenicillamine had no effect on cGMP accumulation, confirming previous studies that these cells lack soluble guanylate cyclase activity. Hemoglobin and FeSO4/ascorbate, agents that inhibit the actions of nitric oxide, both decreased S-nitroso-N-acetylpenicillamine-induced antimitogenesis, supporting the view that this effect was related to the generation of nitric oxide. The antimitogenic activity of S-nitroso-N-acetylpenicillamine was unlikely to be the expression of nitric oxide-induced degradation of serum mitogens, as indicated by the decrease of the antimitogenic activity on prolonged preincubation of SNAP in serum-containing medium. We conclude that nitric oxide-generating vasodilators inhibit serum-induced mitogenesis and cell proliferation in BALB/c 3T3 fibroblasts by a cGMP-independent mechanism.