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The possible role of calmodulin in the control of prolactin secretion was examined. The effects of a wide variety of agents on inhibition of prolactin secretion from isolated rat anterior pituitary cells and inhibition of calmodulin activity in an in-vitro system (calmodulin-activated cyclic GMP phosphodiesterase) were compared. A number of phenothiazines showed a close correlation of potencies in the two systems, as did the more specific calmodulin antagonist, N-(6-aminohexyl)-5-chloro-1-naphthalene sulphonamide (W7), suggesting that calmodulin may be involved in the control of prolactin secretion. Some other drugs also inhibited both prolactin secretion and calmodulin activity in addition to their other well-characterized biochemical effects. However, many of these drugs (including two phenothiazines) were more potent inhibitors of prolactin secretion than of calmodulin activity, suggesting that other intracellular systems in addition to calmodulin may be involved in the control of the secretory process.