Nitroprusside inhibits serotonin-induced mitogenesis and tyrosine phosphorylation of smooth muscle cells.
Serotonin (5-hydroxytryptamine, 5-HT) produces hyperplasia and hypertrophy 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 cellular adenosine 3',5'-cyclic monophosphate or inhibit 5-HT transport or tyrosine phosphorylation. A rapid enhancement of tyrosine phosphorylation of a 120-kDa protein (p120) is associated with the 5-HT-induced mitogenesis. In the present studies, sodium nitroprusside (SNP, 10-100 micromol/l), a NO-generating agent, dose dependently inhibited 5-HT-induced thymidine incorporation by SMC. Inhibition of the 5-HT stimulatory effect was also observed with isosorbide dinitrate and nitroglutathione, which are also NO donors. Incubation of cells with 8-bromoguanosine 3',5'-cyclic monophosphate (1 micromol/l) mimicked the antimitogenic action of SNP. The antiproliferative effect of SNP was inhibited by hemoglobin (50 micromol/l) and potentiated by superoxide dismutase (200 U/ml), supporting the role of NO in the process. Enhancement of tyrosine phosphorylation of p120 by 5-HT was prevented by preincubation with SNP or exogenously added guanosine 3',5'-cyclic monophosphate. The data indicate that 5-HT acts as a mitogen for SMC through a signal transduction pathway involving tyrosine phosphorylation. SNP likely prevents the 5-HT-induced mitogenesis of SMC through elevation of intracellular guanosine 3',5'-cyclic monophosphate and inhibition of tyrosine phosphorylation of p120.
Lee
S L
SL
Pulmonary and Critical Care Division, New England Medical Center, Boston, Massachusetts 02111, USA.
Wang
W W
WW
Fanburg
B L
BL
D000199:Actins / Q000096:biosynthesis; D000818:Animals; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D006965:Hyperplasia; D006984:Hypertrophy; D007548:Isosorbide Dinitrate / Q000494:pharmacology; D007700:Kinetics; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011190:Potassium Cyanide / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D011651:Pulmonary Artery; D012701:Serotonin / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism
D000199:Actins; D010750:Phosphoproteins; D016271:Proto-Oncogene Proteins c-myc; D012702:Serotonin Antagonists; D009599:Nitroprusside; D019000:Phosphotyrosine; D012701:Serotonin; D004247:DNA; D013482:Superoxide Dismutase; D007548:Isosorbide Dinitrate; D011190:Potassium Cyanide; D013936:Thymidine