A role for adrenergic receptors in the uterotonic effects of ergometrine in isolated human term non-laboring myometrium

Background: Ergometrine is a uterotonic agent that is recommended in the prevention and management of post partum hemorrhage. Despite its long-standing use the mechanism by which it acts in humans has never been fully elucidated. The objective of this study was to investigate the role of adrenoreceptors in ergometrine's mechanism of action in human myometrium. The study examined the hypothesis that alpha adrenoreceptor antagonism would result in the reversal of the uterotonic effects of ergometrine. Methods: Myometrial samples were obtained from women undergoing elective cesarean delivery. The samples were then dissected into strips and mounted in organ bath chambers. Following generation of an ergometrine concentration-response curve (10-15 to 10-5 M), strips were treated with increasing concentrations of ergometrine (10-15 to 10-7 M) alone and ergometrine (10-7 to 10-5 M) in the presence of phentolamine (10-7 M), prazosin (10-7 M), propranolol (10-6 M) or yohimbine (10-6 M). The effects of adding ergometrine and the effect of drug combinations were analysed using linear mixed effects models with measures of amplitude (g), frequency (contractions/10min) and motility index (g*contractions/10min). Results: A total of 157 experiments were completed on samples obtained from 33 women. There was a significant increase in the motility index (adding 0.342 g*counts/10min/µM; 95% CI from 0.253 to 0.431, P<0.001), amplitude (0.078 g/µM; 95% CI, from 0.0344 to 0.121, P=5e-04) and frequency (0.051 counts/10min/µM; 95% CI, 0.038 to 0.063, P<0.001) in the presence of ergometrine. The α adrenergic antagonist phentolamine and the more selective α1 adrenergic antagonist prazosin, inhibited the ergometrine mediated increase in motility index, amplitude and frequency (-1.63 g*counts/10mins/µM and -16.70 g*counts/10mins/µM for motility index, respectively). Conclusions: These results provide novel evidence for a role for α adrenergic signaling mechanisms in the action of ergometrine on human myometrial smooth muscle in the in vitro setting. Information that sheds light on the mechanism of action of ergometrine may have implications for the development of further uterotonic agents.