Structure-function relationship of calcium ion channel antagonists at the pituitary gonadotrope.

We have compared the potencies of chemically heterogeneous classes of Ca2+ ion channel inhibitors as antagonists of GnRH-stimulated LH release from the rat pituitary. Verapamil and its more potent derivative methoxyverapamil (D600) are effective inhibitors. The 1,4-dihydropyridines, however, had no antagonistic efficacy, and diltiazem had slight inhibitory action, but only when preincubated with cells before GnRH addition. The observation that the potency series of antagonists was identical (verapanoids greater than diltiazem greater than 1,4-dihydropyridines) whether GnRH or veratridine was used to stimulate the release mechanism is consistent with the premise that the same Ca2+ channel is regulated by the receptor and by agents that evoke gonadotropin release by cell depolarization. This potency series is virtually opposite that observed for muscle tissue. Accordingly, these data suggest that the receptor-regulated Ca2+ ion channel of the pituitary gonadotrope is distinct from that described in muscle.