Role of carboxy-extended forms of oxytocin in the rat uterus in the process of parturition.

The hypothalamic synthetic pathway of oxytocin (OT) involves the synthesis of carboxy-extended forms that serve as intermediate prohormones. We hypothesized that extended forms of OT are synthesized in the late-gestational rat uterus and that they compete for OT receptor binding. Parturition occurs only when the ratio of OT to its extended forms reaches a critical level. We have measured OT and its extended forms using two antisera, one recognizing OT and its extended forms, the other recognizing only mature amidated OT. Uterine tissue concentrations of extended forms of OT were 5- to 30-fold greater than those of OT, and both increased progressively and significantly through late gestation. The ratio of OT to its extended forms did not change significantly. Antagonists of estrogen or progesterone receptors reduced concentrations of extended forms by > 90% and of OT by 50%, though the estrogen antagonist significantly prolonged gestation and the progesterone antagonist induced preterm delivery. Using a muscle bath preparation, extended forms of OT were weak uterine stimulants and did not alter the OT concentration-response curves. Extended forms of OT were two to three orders of magnitude less able than OT to displace radiolabeled OT from late-gestational uterine binding sites. We conclude that uterine carboxy-extended OT prohormones are regulated in part by estrogen and progesterone. However, these extended forms of OT have little direct biological activity and do not compete with OT for receptor binding. Their role in the process of parturition may be confined to acting as substrates for OT synthesis.