ACTIVATION OF ADENYLYL-CYCLASE DOWN-REGULATES SODIUM CALCIUM EXCHANGER OF ARTERIAL MYOCYTES/

Chronic elevation of adenosine 3',5'-cyclic monophosphate (cAMP) is kn own to inhibit the proliferation of cultured vascular smooth muscle ce lls. The present findings show that the activation of adenylyl cyclase with forskolin decreased Na+/Ca2+ exchanger (NCX) mRNA and activity. Fetal bovine serum restored NCX transcript and activity. The changes i n NCX transcript preceded the changes in NCX activity. Incubation of l ow-passage immortalized myocytes with forskolin plus 3-isobutyl-1-meth ylxanthine (IBMX), which inhibits cAMP phosphodiesterase, decreased NC X mRNA by 60% in 6 h and 80% in 24 h. After a 6-h lag, forskolin plus IBMX decreased NCX activity almost linearly to 20% of control at 40 h. 1,9-Dideoxyforskolin, which does not activate adenylyl cyclase, had n o effect on NCX mRNA or activity. Forskolin plus IBMX decreased the c- Myc transcript, an immediate-early gene whose expression correlates wi th cell proliferation, but had no effect on plasma membrane Ca2+ ATPas e transcripts. Removal of forskolin plus IBMX and addition of fetal bo vine serum increased NCX and c-Myc transcripts seven- to eightfold in 6 h and restored NCX activity in 24 h. Inhibition of protein or RNA sy nthesis by cycloheximide or actinomycin D, respectively, prevented the increase in NCX mRNA. In contrast to blocking NCX induction, cyclohex imide potentiated c-Myc induction by serum. Transcription factors that regulate myocyte growth may mediate the opposing influences of serum and forskolin on NCX mRNA and activity.