One of the primary methods used to screen the development of oxytocin antagonists (OTAs) is the rat oxytocic bioassay. The purpose of this study was to determine whether the rat oxytocic bioassay is a good predictor of binding affinity to human and rat uterine oxytocin receptors (OTr). The binding affinities of five OTAs to human and rat uterine OTr were determined and correlated with pA2 values derived from the rat uterine oxytocic bioassay. Human uterine myometrial tissue was obtained from patients at the time of cesarean section. Rat uterine tissue for the OTr assay was taken at Day 21 of pregnancy. OTr assays were accomplished by isolating uterine cell membranes and performing saturation analysis with cold OTAs and tritium-labeled oxytocin. The association constants (Ka; 10(+8)/M) were calculated by nonlinear curve-fitting techniques. The Ka for the five OTAs (Mpa1-OT, Antag I, L366948, Antag II, and Antag III), as estimated from the human OTr assay, were 0.55, 0.60, 2.27, 1.91, and 47.20, respectively. Ka estimates obtained through use of rat uterine membranes were 0.51, 1.16, 5.89, 2.03, and 24.40, respectively. Correlation of the log10 of the rat oxytocic bioassay results with those of the rat and human OTr assay was 0.94 and 0.98, respectively (p < 0.01). Antag III was approximately 55, 48, and 90 times more potent than Mpa1-OT as determined by the rat bioassay and rat and human uterine OTr assays, respectively. Mpa1-OT is an OTA that is currently undergoing clinical evaluation.(ABSTRACT TRUNCATED AT 250 WORDS)

Modulation of virus expression has been reported following exposure to a variety of cellular stresses, including UV radiation and heat-shock. The experiments reported here were designed to examine expression of endogenous VL30 (virus-like 30 S) elements following exposure of whole mice to ionizing radiations. Whole mice were exposed to doses of neutrons (50 cGy) or gamma-rays (300 cGy) shown to be equally efficient in cancer production in the whole animal, and tissues were harvested at 10 and 60 min following completion of the exposure. RNA extracted from these tissues and from tissues of untreated controls was examined for VL30 RNA accumulation by dilution dot blot and Northern blot analyses. These studies revealed that neutrons repressed VL30 RNA accumulation evident within 10 min following exposure in brain, gut, thymus and spleen but not in liver, in which VL30 RNA was unaffected by radiation exposure. During this same time interval, gamma-rays induced VL30 expression in gut and brain and to a lesser extent in liver. These experiments suggest the presence of a differential molecular response following whole-body exposure to high- versus low-LET radiations. In addition, this work demonstrates that ionizing radiations may affect expression of murine endogenous viral sequences.