NO INCREASES PROTEIN-TYROSINE-PHOSPHATASE ACTIVITY IN SMOOTH-MUSCLE CELLS - RELATIONSHIP TO ANTIMITOGENESIS

We investigated the mechanisms of NO-induced antimitogenesis in primar y aortic smooth muscle cells from newborn rats. S-nitroso-N-acetylpeni cillamine (SNAP), an NO-releasing agent, decreased basal and growth fa ctor-stimulated DNA synthesis with a threshold effectiveness of 0.3-3 mu M A second NO-releasing agent, 3-morpholinosydnonimine-N-ethylcarba mide, a hydrolysis-resistant cyclic nucleotide, 8-bromo-guanosine 3',5 '-cyclic monophosphate (8-BrcGMP), and atrial natriuretic peptides eli cited a similar effect, whereas 8-bromo-adenosine 3',5'-cyclic monopho sphate (8-BrcAMP) was ineffective, supporting the view that NO and cGM P, but not cAMP, mediated at least some of SNAP's antimitogenic effect . SNAP and 8-BrcGMP decreased the levels of phosphotyrosine, especiall y in proteins of 70-85 kDa and similar to 215 kDa molecular mass. SNAP decreased protein phosphotyrosine levels with a threshold effectivene ss similar to that of its antimitogenic effect. Moreover, SNAP increas ed protein tyrosine phosphatase (PTPase) activity in cell homogenates, indicating that phosphotyrosine dephosphorylation was likely to be th e result of increased PTPase activity. Peroxovanadate, a selective PTP ase inhibitor, blocked the antimitogenic effect of 8-BrcGMP, suggestin g that loss of protein phosphotyrosine and antimitogenesis were causal ly linked. These findings describe a potential mechanism for NO-induce d antimitogenesis in aortic smooth muscle cells in primary culture.