In vascular smooth muscle cells the phorbol ester, 12-O-tetradecanoyl phorbol 13-acetate (TPA), a potent activator of C-kinase, inhibited the accumulation of inositol phosphates and the mobilization of calcium produced by several agonists. In the same way, TPA inhibited the fluoride-induced activation of phosphoinositide metabolism. These results suggest a C-kinase action at a post-receptor level. Moreover, the fluoride-induced accumulation of inositol phosphates shows the presence of one or more guanine nucleotide-binding proteins (G-proteins) in the regulation of receptor-phospholipase C coupling. This was confirmed by the use of N-ethylmaleimide and pertussis toxin. These results support the view that, in addition to the induction of sustained contractions, C-kinase can activate negative feedback mechanisms in aortic myocytes.