The mechanisms underlying Bay K 8644-stimulated phasic myometrial contractions.
OBJECTIVE
Phasic myometrial 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 normalized 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 significant 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.
Chien
E K
EK
Department of Obstetrics and Gynecology, University of Chicago, Illinois 60637, USA.
Saunders
T
T
Phillippe
M
M
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology*; D000225:Adenine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology; D020746:Calcium Channels, L-Type; D004533:Egtazic Acid / Q000494:pharmacology; D004971:Estrus; D005260:Female; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism; D007537:Isometric Contraction / Q000187:drug effects; D008954:Models, Biological; D009215:Myometrium / Q000187:drug effects / Q000502:physiology*; D009543:Nifedipine / Q000494:pharmacology; D010121:Oxytocin / Q000494:pharmacology; D011359:Proestrus; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014590:Uterine Contraction / Q000187:drug effects*
D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D007295:Inositol Phosphates; D010121:Oxytocin; D004533:Egtazic Acid; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D009543:Nifedipine; D000225:Adenine; D002118:Calcium