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Calcium Channel Agonists and Antagonists: Effects of Chronic Treatment on Pituitary Prolactin Synthesis and Intracellular Calcium

Department of Pharmacology and the Cancer Center, University of Rochester School of Medicine and Dentistry Rochester, New York 14642
Department of Physiology and Biophysics, Mt. Sinai School of Medicine New York, New York 10029

Address requests for reprints to: Dr. Patricia M. Hinkle, Department of Pharmacology, The University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, New York 14642.

Abstract

PRL synthesis by GH cells in culture has previously been shown to increase when calcium is added to cultures grown in calcium-depleted medium or when cultures are treated for 18 h or longer with the dihydropyridine calcium channel agonist BAY K8644, whereas the antagonist nimodipine inhibits PRL. The experiments described here were designed to test whether differences in PRL synthesis caused by the dihydropyridines are due to changes in PRL mRNA levels, whether structurally different classes of calcium channel blockers alter PRL production, and whether long term treatment with calcium channel agonists and antagonists alters intracellular free calcium, [Ca²⁺]_i. PRL synthesis and PRL mRNA levels were increased similarly by BAY K8644 and decreased in parallel by the dihydropyridine antagonist nimodipine, while overall protein and RNA synthesis were not changed by either the agonist or antagonist. Two calcium channel blockers which act at different sites on L-type channels than the dihydropyridines also inhibited PRL synthesis without affecting GH; 5 µM verapamil reduced PRL by 64% and 15 µM diltiazem by 89%. Partial depolarization with 5–25 mM KCI increased PRL synthesis up to 2-fold. The intracellular free calcium ion concentration was estimated by Quin 2 and averaged 142 nivi for control cultures in normal medium, and 128 and 168 nM for cultures treated 72 h with nimodipine or BAY K8644, respectively. Nimodipine totally prevented the calcium rise obtained upon depolarization. The resting intracellular calcium concentration and PRL synthesis were lower for cultures grown in serum-free medium with no added calcium (85 nM [Ca²⁺]_i, 1.88 µg PRL) than for those grown in serum-free medium with added calcium and BAY K8644 (400 nM [Ca²⁺]_i, 6.75 µg PRL). These data support the conclusion that drugs like the dihydropyridines, verapamil, and diltiazem regulate PRL synthesis selectively via an effect on PRL mRNA levels and that this results from actions at L-type voltage sensitive calcium channels.

FOOTNOTES

This research was supported in part by NSF Grant DCB-8544786 (to C.B.), NIH Grants DK-19974 (to P.M.H.) and GM-36847 (to C.B.), Cancer Center Core Research Grant CA-11098 (to P.M.H.) and National Research Service Award Fellowship DK-08071 (to A.E.J.).

Received for publication July 8, 1988. Accepted for publication August 5, 1988.

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