Loss of prostaglandin F2α, but not thromboxane, responsiveness in pregnant human myometrium during labour

Abstract

Prostaglandins (PG) E 2 , PGF 2a and thromboxane (TX) mediate uterine contractility by targeting prostonoid EP, FP and TP receptors respectively. The aim of this study was to elucidate the function of these receptors in isolated human myometrium taken at term gestation prior to and following labour onset. Lower segment myometrial strips were immersed in organ baths in oxygenated Krebs' solution at 37 8C and connected to isometric force transducers. After equilibration, spontaneous activity and concentration responses to PGE 2 , PGF 2a and U46619 (a stable TX mimetic) were measured as area under the curve and expressed as a percentage of the final contraction induced by hypotonic shock. Results were expressed as arithmetic meansGS.E.M. and analysed using two-way ANOVA with Bonferroni's post hoc test. Myometrium excised at late gestation displayed the greatest spontaneous activity compared with the tissues taken during labour (P!0 . 001). Excitation evoked by PGF 2a (P!0 . 01) and PGE 2 at 10 K5 mol/l were attenuated after labour onset. U46619 consistently stimulated concentration-dependent contractions (P!0 . 001) and selective antagonists confirmed TP-mediated effects. The maintained responses to TX indicate crucial roles for TP receptors in the muscular tonus of the parturient uterus. This receptor and its secondary messenger system represent effective myometrial targets for tocolytic agents in both pregnancy and labour-associated disorders.

Prostanoid receptor antagonists: development strategies and therapeutic applications

“…Recent studies on human myometrial specimens obtained at parturition provide a new perspective. It appears that there is a marked alteration in prostanoid receptor functional dynamics at term, prior to and following the onset of labour (Fischer et al. , 2008).…”

Characterization of the myometrial transcriptome and biological pathways of spontaneous human labor at term

“…Evidence suggests that in preparation for labor, the myometrium attains an increasingly contractile phenotype, [27, 29, 53, 55, 59, 62, 66, 68, 100, 103, 106, 108, 110, 112, 113, 122–124, 146, 174, 177, 179, 181, 183, 188, 190, 196, 216, 225, 280–282, 296, 310, 315, 321] while the cervix undergoes preparatory changes including cervical ripening and dilatation [61, 68, 112, 113, 132, 134, 143, 147, 151, 176, 184, 185, 218, 219, 225, 272, 275, 276, 282, 296, 297, 311, 312, 321, 330, 337]. Labor disorders such as preterm labor and abnormal parturition at term represent abnormalities of one or more components of the common pathway of parturition and are associated with increased morbidity and mortality [101, 102, 117, 118, 121, 148].…”

International Union of Basic and Clinical Pharmacology. LXXXIII: Classification of Prostanoid Receptors, Updating 15 Years of Progress

“…TxA 2 is a potent constrictor of bronchial smooth muscle and has been implicated in both asthma and chronic obstructive pulmonary disease (Ro- , 2006). TP receptors are also uterotonic (Senior et al, 1991) and seem to be particularly important in parturition, because PGF 2␣ responsiveness, but not that of TxA 2 , is lost in the human myometrium during labor (Fischer et al, 2008). Finally, on the smooth muscle cell theme, TP receptors seem capable of differentiating human stem cells to smooth muscle-like cells .…”

“…Ramatroban has been reported to attenuate cough in subjects with cough variant asthma (Kitamura et al, 2003a). The potential use of TP antagonists for treating preterm labor is not new but deserves new impetus based on recent findings on the human myometrium that PGF 2␣ responsiveness, but not TxA 2 responsiveness, of the uterus is lost during labor (Fischer et al, 2008). The most recent potential uses for TP antagonists are listed in Table 10.…”