DualEffect ofSerotonin on GrowthofBovine Pulmonary Artery SmoothMuscle Cells inCulture

Wehavepreviously reported thatserotonin (5-hydroxytryptamine (SHT)) alters cultured bovine pulmonary artery smoothmusclecell(SMC)configuration through twodifferent regulatory mechanisms. We now report that5HT alsoregulates SMC growththrough these same two mechanisms-a stimulatory eventinitiated intracellularly andinhibition ofgrowth resulting froma cell surface action. 5HT(1,M) plus0.1mM iproniazid (a5HTmetabolic inhibitor) produced a severalfold stimulation ofDNA synthesis (asmeasured by('H)thymidine incorpo- ration) ofSMCsafter a 17-24-hour incubation withonly a slight elevation ofcellular cAMP. Thisstimulatory effect responded synergistically withother growth factors including platelet- derived growth factor, fibroblast growth factor, andepidermal growth factor andwas effectively reversed by5HT uptakeinhibition. Itwas notproduced by5-hydroxyindoleacetic acid, a metabolite of5HT.Inthepresenceof1pM 5HTplus0.1mM isobutylmethylxanthine (IBMX), cAMP was elevated eightfold, dendritic formation occurred, and('H)thymidine labeling of SMCswas inhibited. Inhibition oflabeling by('H)thymidine was mimickedbyotheragents that elevated cellular cAMP(10,uMhistamine, 1,Misoproterenol plus0.1mM IBMX,and10,uM forskolin) andby1 mM dibutyryl cAMP.Thisinhibitory effect was notblockedbyeither inhibition of5HT uptake or 5HT-receptor antagonists ketanserin (5HT2); methiothepin, spiperone, andmianserin (5HT1/5HT2); and3-tropanyl-indole-3-carboxylate and3-tropanyl- 3,5-dichlorobenzoate