The possibility that vasoactive intestinal polypeptide (VIP) may facilitate the nicotine-mediated induction of adrenal medullary tyrosine hydroxylase (TH) was investigated with primary cultures (5-7 days in vitro) of bovine adrenal chromaffin (BAC) cells. Exposure of BAC cells to 100 microM nicotine led to only a marginal increase in the amount of TH mRNA, TH protein, and TH activity. VIP, alone or in the presence of a phosphodiesterase inhibitor, produced a marked increase in TH mRNA, TH protein, and TH activity. Moreover, VIP together with nicotine, at concentrations that alone were devoid of effect, increased the amount of TH mRNA and TH activity. A synergistic effect of VIP and nicotine on cAMP accumulation in BAC cells was also apparent. The marginal effects of large doses of nicotine on both cAMP accumulation and TH induction were blocked completely by hexamethonium but were also partially inhibited by the VIP antagonist [p-chloro-D-Phe6,Leu17]-VIP. Nicotine may, therefore, stimulate the release of VIP from cultured BAC cells and VIP, in turn, by increasing cAMP, may synergize with nicotine to enhance TH gene expression.
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