NITROPRUSSIDE INHIBITS SEROTONIN-INDUCED MITOGENESIS AND TYROSINE PHOSPHORYLATION OF SMOOTH-MUSCLE CELLS

Serotonin (5-hydroxytryptamine, 5-HT) produces hyperplasia and hypertr ophy of bovine pulmonary artery smooth muscle cells (SMC) in culture. The growth responses are associated with early elevations of c-myc and actin gene expressions and are blocked by agents that elevate cellula r adenosine 3',5'-cyclic monophosphate or inhibit 5-HT transport or ty rosine phosphorylation. A rapid enhancement of tyrosine phosphorylatio n of a 120-kDa protein (p120) is associated with the 5-HT-induced mito genesis. In the present studies, sodium nitroprusside (SNP, 10-100 mu mol/l), a NO-generating agent, dose dependently inhibited 5-HT-induced thymidine incorporation by SMC. Inhibition of the 5-HT stimulatory ef fect was also observed with isosorbide dinitrate and nitroglutathione, which are also NO donors. Incubation of cells with 8-bromoguanosine 3 ',5'-cyclic monophosphate (1 mu mol/l) mimicked the antimitogenic acti on of SNP. The antiproliferative effect of SNP was inhibited by hemogl obin (50 mu mol/l) and potentiated by superoxide dismutase (200 U/ml), supporting the role of NO in the process. Enhancement of tyrosine pho sphorylation of p120 by 5-HT was prevented by preincubation with SNP o r exogenously added guanosine 3',5'-cyclic monophosphate. The data ind icate that 5-HT acts as a mitogen for SMC through a signal transductio n pathway involving tyrosine phosphorylation. SNP likely prevents the 5-HT-induced mitogenesis of SMC through elevation of intracellular gua nosine 3',5'-cyclic monophosphate and inhibition of tyrosine phosphory lation of p120.