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The Mechanisms Underlying Bay K 8644—Stimulated Phasic Myometrial Contractions

Department of Obstetries and Gynecology, MC 2050, University of Chicago Hospital, 5841 S. Maryaland Avenue, Chicago, Illinois

T. Saunders

M. Phillippe, MD

Department of Obstetries and Gynecology, University of Chicago, Chicago, Illinois

Objective: Phasic myometrical contractions appear to be produced by calcium transients resulting from the activation of the phosphatidylinositol-signaling pathway. Bay K 8644, an L-type calcium channel activator, produces an increase in frequency and intensity of phasic myometrial contractions. These studies were performed to test the hypothesis that Bay K 8644-stimulated contractions were mediated through mechanisms involving phosphoinositide-specific phospholipase C activation and cytosolic calcium oscillation-like mechanisms.

Methods: In vitro contraction studies and intracellular calcium imaging were performed on longitudinal strips of uterine tissue obtained from mature virgin Sprague-Dawley rats. Isometric contraction data were computer digitized, analyzed for contraction area, and nomalized for cross-sectional area. Dose-response studies were performed using previously reported inhibitors of cytosolic calcium oscillation mechanisms. In addition, qualitative inositol-phosphate production studies were performed after prelabeling uterine tissue in vitro with ³H-inositol. Subsequently, the labeled inositol phosphates were separated and recovered using anion exchange chromatography.

Results: Bay K 8644 produced periodic calcium transients or oscillations along with a dose-related increase in contractile activity and a signfificant increase in inositol-phosphate production. In contrast, neomycin (an inhibitor of phospholipase C), adenine (an inhibitor of calcium-induced calcium release), nifedipine (an L-type calcium channel blocker), and EGTA (a calcium chelator) significantly inhibited Bay K 8644-stimulated contractile activity.

Conclusions: These results are consistent with the hypothesis that Bay K 8644, through its facilitation of increased intracellular calcium, results in the activation of the phosphatidylinsitol-signaling pathway and cytosolic calcium oscillation-like phenomena, thereby resulting in the generation of phasic myometrial contractions.

Key Words: Bay K 8644 • inositol phosphates • intracellular calcium • phospholipase C • myometrial contractions

Journal of the Society for Gynecologic Investigation, Vol. 3, No. 3, 106-112 (1996)
DOI: 10.1177/107155769600300302


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