The objective of this study was to investigate the effects of abnormal cannabidiol (abn-cbd) on oxytocin-induced myometrial contractility occurring during pregnancy. Isometric tension recordings were performed in isolated myometrial strips from biopsies obtained at elective cesarean section. The effects of cumulative doses of abn-cbd (10−9–10−5 M) on oxytocin-induced myometrial contractions alone, and on those following pre-incubation with SR 144528, AM 251, methylene blue, and iberiotoxin were measured, and dose–response curves were constructed. The pD2 (−log EC50) values and the maximal inhibitory (MMI) values that were achieved were compared for each tissue type. Abn-cbd exerted a potent relaxant effect on oxytocin-induced myometrial contractions in vitro. Pre-incubation with the guanylate cyclase inhibitor, methylene blue, and the BKCa channel antagonist, iberiotoxin, significantly attenuated this effect (for pD2, P<0.01; for MMI, P<0.01). Abn-cbd exerts a potent inhibitory effect on human uterine contractility. This effect is partially mediated through modulation of guanylate cyclase and activation of BKCa channel activity. These findings have implications for physiologic regulation of myometrial quiescence.
Diarmaid D Houlihan, Michael C Dennedy and John J Morrison
Anne M Friel, Donal J Sexton, Michael W O’Reilly, Terry J Smith and John J Morrison
Pre eclampsia represents a state of increased or prolonged vasoconstriction, partially linked to the potent vasocontractile effect of isoprostanes. The process of Rho A-mediated calcium sensitisation is inherent to a state of prolonged contractility in many smooth muscle types. The aim of this study was (1) to investigate mRNA expression levels of Rho A and Rho kinase isoforms (I and II) in the umbilical artery from normotensive and pre eclamptic women and (2) to determine whether the effects of two isoprostanes, 8-iso prostaglandin F2α (8-iso PGF2α) and 8-iso prostaglandin E2 (8-iso PGE2), on umbilical artery tone, were mediated via the Rho kinase pathway. Real-time RT-PCR using primers for Rho A, ROCK I and ROCK II was performed on total RNA isolated from umbilical artery specimens obtained from normotensive and pre eclamptic women. The effects of both isoprostanes (n = 6) (in the absence and presence of the specific Rho kinase inhibitor Y-27632), on umbilical artery tone were measured, and compared with control recordings. Rho A mRNA expression levels were significantly lower in umbilical artery samples obtained from pre eclamptic women (n = 4) in comparison to those from normotensive women (n = 6) (P < 0.05). ROCK I and ROCK II mRNA levels were similar in both vessel types (P > 0.05). Both isoprostanes exerted a significant concentration-dependent vasocontractile effect (n = 7) (P < 0.001) on umbilical artery. For 8-iso PGE2, this effect was antagonised by Y-27632 (n = 6) (P < 0.01). The significant reduction of Rho A mRNA levels in umbilical arteries from pregnancies complicated by pre eclampsia may serve to counteract the diminished perfusion associated with the pathophysiology of pre eclampsia. The vasocontractile effect of 8-iso PGE2 in pre eclampsia may in part be mediated via the Rho kinase pathway.