Modification of the rat uterine response to oestrogen and tamoxifen by thromboxane antagonists

Abstract

1 The thromboxane receptor antagonists EP092, AH23848 and BM 13.505 were used to investigate the role of thromboxane in the uterotrophic response to oestradiol and tamoxifen. 2 The parameters examined were uterine blood flow (measured by the microsphere technique), uterine wet and dry weights and the concentrations of cytosolic and nuclear oestrogen receptors. 3 Only EP092 potentiated the hyperaemic response to oestrogen but all three thromboxane antagonists inhibited oestradiol-stimulated uterine growth. This inhibition was accompanied by a decrease in nuclear oestrogen receptor concentration. 4 The uterotrophic response to tamoxifen was unaffected by the thromboxane antagonists. 5 The mechanism by which the thromboxane antagonists may be exerting their growth inhibitory effect is discussed, although, whether this effect can be attributed to blockade of thromboxane receptors or to some other mechanism is not clear from this study.

The effects of thromboxane receptor antagonists on oestrogen‐induced uterotrophic responses in the spontaneously hypertensive rat

“…This phenomenon was also observed, but to a lesser extent, in the CD (Kerr et al, 1991). Interestingly, the total receptor level was lower in the SHR uterus than the CD, even though the weight of the uterus in the SHR is higher than that of the CD when normalised for body weight (Kerr et al, 1991). This paucity of oestrogen receptors in the SHR may explain the increased sensitivity seen to thromboxane antagonists in inhibiting the dry weight response in the uterus.…”

“…In the cases of AH23848 and BM 13.505, this phenomenon could be ascribed to the fact that both these compounds have been shown to be partial agonists (Brittain et al, 1985;Patscheke et al, 1987). However, there have been no reports of EP092 displaying partial agonist activity and in the normotensive CD strain this compound was found to enhance the oestradiol-stimulated hyperaemia (Kerr et al, 1991). It is possible that due to the time lag between drug administration and blood flow analysis, adaptive regulatory vascular changes have occurred in the SHR which counteract the influence of the thromboxane receptor blockade.…”

“…Thus while it would appear that basal vascular thromboxane levels show no significant strain differences (when the antagonists were used without oestradiol they had no effect on blood flow in either species), the thromboxane synthetic capacity of the SHR may exhibit altered reactivity under oestrogen stimulated conditions. Oestradiol-induced water imbibition also appears to be more sensitive to the inhibitory actions of the thromboxane antagonists than the equivalent response in the CD rat (Kerr et al, 1991). Thromboxane has been implicated in the induction of lysosomal instability (Dorn & Halushka, 1985) and such activity may contribute to the eosinophil-mediated (Tchernitchin et al, 1989) uterine oedematous response.…”