Role of inositol phospholipid hydrolysis in the initiation of agonist-induced contractions of rat uterus: effects of domination by 17 beta-estradiol and progesterone.
The role of inositol phospholipid (IP) hydrolysis in agonist-mediated contractility was examined in rat uterine smooth muscle by comparing carbachol-, oxytocin-, and PGF2 alpha-mediated [3H]IP accumulation and tension generation. In both estrogen- and progesterone-dominated uteri, all three agonists exhibited dose-dependent contractile responses. Agonist potencies (EC50 values) for eliciting [3H]IP accumulation or contractile responses were found to be very similar and did not change significantly between hormonal states. Maximal responses of agonist-mediated [3H]IP accumulation and tension generation were significantly affected by the endocrine state of the uterus and were dependent on the agonist examined. Maximal carbachol- and PGF2 alpha-induced [3H]IP accumulation were found to be elevated in estrogen-dominated relative to progesterone-dominated uteri, whereas maximal forces generated by these two agonists were smaller in progesterone-dominated relative to estrogen-dominated tissues. Oxytocin-induced responses did not differ between hormonal states. To determine whether these differences between [3H]IP accumulation and contractility responses could be attributed to changes in receptor-mediated signal transduction mechanisms, receptor expression and coupling to phospholipase C were studied. Myometrial muscarinic and oxytocin receptors assessed by radioligand binding were found to have three- to four-fold greater capacities in estrogen-dominated than in progesterone-dominated uteri without significant changes in agonist affinities. Agonist-mediated [3H]IP accumulation was potently inhibited by both pertussis and cholera toxins in both hormonal states. These experiments show that estrogen- and progesterone-dominated environments regulate both uterine excitability and contractility and that the mechanisms of this regulation are complex and dependent on the agonist system stimulated.
Ruzycky
A L
AL
Department of Medicine, Harvard Medical School, Beth Israel Hospital, Boston, MA 02215.
Crankshaw
D J
DJ
D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D015237:Dinoprost; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D006868:Hydrolysis; D066298:In Vitro Techniques; D010121:Oxytocin / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism*; D011374:Progesterone / Q000494:pharmacology*; D011460:Prostaglandins F / Q000494:pharmacology; D051381:Rats; D014590:Uterine Contraction / Q000187:drug effects*; D014599:Uterus / Q000187:drug effects / Q000378:metabolism
D010716:Phosphatidylinositols; D011460:Prostaglandins F; D011374:Progesterone; D004958:Estradiol; D010121:Oxytocin; D002217:Carbachol; D015237:Dinoprost