Effects of magnesium ion and oxytocin inhibitors on the uterotonic activity of oxytocin and prostaglandins E2 and F2ALPHA.

The uterotonic activity of oxytocin and prostaglandins E2 (PGE2) and F2α (PGF2α) was studied in isolated rat uterine preparations. In single injections and at low dose levels, both oxytocin and prostaglandins (PGs) produced similar patterns of response. However, at higher dose ranges as applied in the cumulative dose-response procedure, the uterine contractions induced by PGs were irregular and accompanied by a greater hypertonus as compared to that induced by oxytocin. The maximal responses attained were about equal with both compounds. It was found that [1-L-penicilamine]oxytocin, a specific inhibitor of the uterotonic response to oxytocin, had no inhibitory effect on the activity of PGs. On the contrary, in a few instances but not invariably, the utenotonic activity of PGs was enhanced by [1-L-penicillamine]oxytocin. It. was further observed that when a dose of oxytocin and a dose of PGE2 were injected together, a synergistic response was produced. The effect of Mg++ on the activity of oxytocin and PGs was both quantitatively and qualitatively different. The potency of oxytocin was markedly enhanced by 0.5 and 1.0 mM Mg++ in the bathing medium. In 0.5 mM Mg++ both the potency of oxytocin and the maximal response increased. In 0.5 mM Mg++ the response to PGE2 was slightly reduced, but not statistically significantly, where 1.0 mM Mg++ markedly reduced the potency of PGE2 without affecting the maximal response. The response to PGF2α was not significantly affected by either 0.5 or 1.0 mM Mg++. These findings suggest that the receptor for oxytocin and the receptor for PGs are separate and distinct and that oxytocin and PGs may each activate a different receptor-response mechanism. The effects of Mg++ on the activity of a series of oxytocin inhibitors. [1-L-penicilamine]oxytocin, [2,4-dileucine]oxytocin, [2-phenylalanine, 4-leucine]oxytocin and [2-isoleucine, 4-leucine]oxytocin, were also studied. Previous work has shown that there appeared to be an inverse relationship between the Mg++ potentiating effect and the potency of oxytocin analogs, and it has been suggested that Mg++ increased the peptidereceptor affinity. This relationship was not found to extend to analogs with inhibitory activity. A strong inhibitor such as [1-L-penicillamine]oxytocin was found to suffer a loss of inhibitory activity in the presence of 1.0 mM Mg++. Weak inhibitors such as [2-phenylalanine, 4-leucine]oxytocin and [2-isoleucine, 4-leucine]oxytocin not only lost all their inhibitory activity but on the contrary became active agonists. These observations suggest that the potentiating effect of Mg++ on active neurohypophysial peptides cannot be satisfactorily explained on the basis of enhancing hormone-receptor affinity alone. Since Mg++ increases the potency as well as the maximal response to oxytocin, it is probable that Mg++ may in some manner also increase the reactivity on reduce the threshold of excitation-contraction coupling in the contractile system sensitive to the neumohypophysial peptides.