Role for cyclic adenosine monophosphate in the synergistic interaction between oxytocin and corticotrophin-releasing factor in isolated human gestational myometrium.

Abstract

We wished to investigate the role of cAMP in the synergistic effect of corticotrophin-releasing factor and oxytocin on human myometrial contractility. Isolated human gestational myometrium obtained from Caesarean sections at term was studied in vitro. Static incubation techniques as well as tension recordings were applied to the tissue obtained. The subjects were healthy pregnant women undergoing lower segment Caesarean section at term, prior to labour. Specimens obtained were immediately dissected into small strips and either incubated in multi-well trays (strip weight 2.75 mg) or superfused and used for tension recordings (strip weight 2.00 mg). cAMP accumulation was measured after incubation with oxytocin (0.1-10 nM), corticotrophin-releasing factor (1 nM) or a combination of both peptides. Tension generated by the muscle strips was recorded isometrically and response to oxytocin (0.01-10 nM), corticotrophin-releasing factor (1 nM) and forskolin (10 nM) expressed in force per gram wet tissue (N/g). Oxytocin (0.1 nM) causes a statistically significant dose-related decrease in cAMP when combined with 1 nM corticotrophin-releasing factor (P less than 0.001), as compared with cAMP stimulation by corticotrophin-releasing factor alone. Time course studies suggest a maximal effect at 1 minute. The hypothesis that an intracellular reduction of cAMP is a prerequisite for the synergistic response in contraction force was tested with tension recordings. Prevention of a decrease in cAMP in the tissue by addition of 10 nM forskolin to the superfusate abolished the potentiation between oxytocin and corticotrophin-releasing factor. These results indicate that a fall in cAMP concentration plays a vital mediating role in the synergistic interaction between oxytocin and corticotrophin-releasing factor.