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 dose 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 polypeptide (VIP), which shows a considerable homology with PACAP, also inhibited dose dependently the AVP-induced DNA synthesis in a cell cycle dependent manner. The maximum inhibition was also observed at the late 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 aortic SMC. VIP also stimulated cAMP accumulation, and the accumulation by a combination of PACAP and VIP was not additive. Both PACAP and VIP had little effect on phosphoinositide hydrolysis in these cells. The suppression of the AVP-induced DNA synthesis by PACAP or VIP was enhanced by 3-isobutyl-1-methylxanthine, an inhibitor for phosphodiesterases. Dibutyryl cAMP, but not 8-bromo-cGMP, inhibited the AVP-induced DNA synthesis, and a combination of PACAP and dibutyryl cAMP was not additive. [Ac-Tyr1,D-Phe2]growth hormone-releasing factor, an antagonist for VIP receptor, reversed the inhibitory effect of PACAP on the AVP-induced DNA synthesis. These results suggest that PACAP has an antiproliferative effect on aortic SMC at the late G1 phase of the cell cycle through cAMP production, and that PACAP and VIP inhibit the AVP-induced DNA synthesis by a common mechanism.