Heterologous regulations of cAMP responses in pregnant rat myometrium. Evolution from a stimulatory to an inhibitory prostaglandin E2 and prostacyclin effect.

The regulation of cAMP generation in rat myometrium during gestation was investigated comparatively to the stimulations evoked in the estrogen-dominated myometrium. At the onset of gestation, there was a progressive attenuation in both tissue cAMP accumulation and adenylate cyclase activation in response to isoproterenol and prostaglandins (PGs) (PGE2 and prostacyclin, PGI2), as well as to cholera toxin and to forskolin. Minimal responses were observed at midgestation (day 12). The decline in isoproterenol-mediated cAMP accumulation could not be ascribed to alterations in either beta-adrenergic receptor density or coupling properties. Treatment of day 12 myometrium with islet-activating protein (IAP), pertussis toxin, caused a reversal of the attenuated beta-adrenergic--as well as cholera toxin--responses, suggesting that the inhibitory regulatory protein, Gi, was involved. However IAP treatment did not improve the PGE2-mediated stimulatory effect. In membranes from day 12 myometrium, the amount of [32P]NAD incorporated by IAP into the Mr = 41,000 peptides (alpha i, subunit of Gi was markedly increased compared to membranes from day 0 tissue. There was also a consistent decrease (25%) of the label incorporated by cholera toxin into the Mr = 52,000 (major) and 45,000/53,000 (minor) peptides (alpha s, subunit of Gs). The advanced stages of gestation were associated with a progressive restoration of cAMP responses to isoproterenol, cholera toxin, and forskolin with a full responsiveness before parturition (day 22). By contrast, the inability of PGE2 to generate any active Gs (stimulatory regulatory protein)-C complex persisted and coincided with the development of PGE2-induced inhibition of cAMP generation due to isoproterenol. The inhibitory effect, which was similarly evoked by PGE2 as well as by PGI2 and PGF2 alpha, was prevented by IAP. The data suggest that alterations of the stimulatory Gs-mediated pathway, which culminated at midgestation, is due at least in part to an increase in the abundance of Gi relative to Gs. Additional alterations operate at the level of the prostaglandin receptor(s) with a conversion from a stimulatory (Gs-mediated) cAMP response in the estrogen-dominated myometrium to an inhibitory (Gi-mediated) effect, fully expressed in the final stage of gestation.