EFFECT OF PITUITARY ADENYLATE-CYCLASE ACTIVATING POLYPEPTIDE ON VASOPRESSIN-INDUCED PROLIFERATION OF AORTIC SMOOTH-MUSCLE CELLS - COMPARISON WITH VASOACTIVE INTESTINAL POLYPEPTIDE

Pituitary adenylate cyclase activating polypeptide (PACAP) inhibited d ose dependently the DNA synthesis stimulated by arginine vasopressin ( AVP) in cultured rat aortic smooth muscle cells (SMC). The inhibition was cell cycle dependent and the maximum inhibition was observed when added at the late G1 phase of the cell cycle. Vasoactive intestinal po lypeptide (VIP), which shows a considerable homology with PACAP, also inhibited dose dependently the AVP-induced DNA synthesis in a cell cyc le dependent manner. The maximum inhibition was also observed at the l ate G1 phase. The patterns of both the dose-dependent inhibitions were similar, and the inhibition by a combination of PACAP and VIP was not additive. PACAP stimulated dose dependently cAMP accumulation in aort ic SMC. VIP also stimulated cAMP accumulation, and the accumulation by a combination of PACAP and VIP was not additive. Both PACAP and VIP h ad little effect on phosphoinositide hydrolysis in these cells. The su ppression of the AVP-induced DNA synthesis by PACAP or VIP was enhance d by 3-isobutyl-1-methylxanthine, an inhibitor for phosphodiesterases. Dibutyryl cAMP, but not 8-bromo-cGMP, inhibited the AVP-induced DNA s ynthesis, and a combination of PACAP and dibutyryl cAMP was not additi ve. Ac-Tyr1,D-Phe 2!growth hormone-releasing factor, an antagonist fo r VIP receptor, reversed the inhibitory effect of PACAP on the AVP-ind uced DNA synthesis. These results suggest that PACAP has an antiprolif erative effect on aortic SMC at the late G1 phase of the cell cycle th rough cAMP production, and that PACAP and VIP inhibit the AVP-induced DNA synthesis by a common mechanism.