Nitric oxide-generating vasodilators inhibit mitogenesis and proliferation of BALB/C 3T3 fibroblasts by a cyclic GMP-independent mechanism.
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.
Department of Pharmacology, New York Medical College, Valhalla 10595.
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D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D006152:Cyclic GMP / Q000502:physiology*; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D006454:Hemoglobins / Q000494:pharmacology; D007548:Isosorbide Dinitrate / Q000494:pharmacology; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D009569:Nitric Oxide / Q000378:metabolism*; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D026423:S-Nitroso-N-Acetylpenicillamine
D006454:Hemoglobins; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D004247:DNA; D010396:Penicillamine; D006152:Cyclic GMP; D007548:Isosorbide Dinitrate; D001205:Ascorbic Acid; D015056:1-Methyl-3-isobutylxanthine