Degree Name

PhD (Doctor of Philosophy)

Program

Biomedical Sciences

Date of Award

December 1997

Abstract

$\beta\sb2$-Adrenoceptor ($\beta\sb2$-AR) agonists, such as terbutaline, are used as tocolytic agents in the treatment of preterm labor. $\beta$-Adrenoceptor stimulation relaxes myometrium through specific receptors coupled through Gs to adenylyl cyclase (AC) that catalyzes the conversion of ATP to cAMP. The purpose of this study was to compare $\beta$-adrenoceptors and cAMP production in cultured human leukocytes and myometrial cells, and to determine the importance of $\beta$-adrenoceptors and cAMP production in isoproterenol-induced myometrial relaxation. $\sp{125}$I-iodopindolol was used to assess $\beta$-adrenoceptor affinity and number cAMP levels were analyzed before and after stimulation by isoproterenol, AlF$\sb4\sp-$, forskolin, and PGE$\sb1$. Isometric recording was used to examine myometrium contraction and relaxation. $\beta$-adrenoceptors in leukocytes and myometrial cells have similar $\sp{125}$I-iodopindolol binding affinity and B$\rm\sb{MAX}$. Both tissues can be stimulated by isoproterenol, but have reserve adenylyl cyclase activity not stimulated by $\beta$-ARs. Cultured human myometrial cells have higher basal AC activity and lower isoproterenol coupled cAMP production than leukocytes. The rank order of $\beta$-adrenoceptor agonist potencies in leukocytes is: isoproterenol $>$ terbutaline $>$ ritodrine. Myometrial cells could not be stimulated by terbutaline or ritodrine. This indicates that the intrinsic activity of $\beta$-adrenoceptor coupled cAMP production is different in these two tissues. Prolonged exposure to 200 nM terbutaline results in a decrease in both $\beta$-adrenoceptor number and isoproterenol-coupled cAMP production in cultured leukocytes and myometrial cells. Signal transduction factors, such as adenylyl cyclase and the PGE$\sb1$ pathway, are not affected by the down-regulation process. Isoproterenol relaxes term myometrium through $\beta\sb2$-ARs without a change in cAMP production. Cultured leukocytes do not completely reflect the activity of $\beta$-adrenoceptor coupled cAMP production to myometrial cultured cells. In myometrium, the presence of $\beta$-ARs does not guarantee stimulation of cAMP production, and cAMP is not an accurate index of myometrial relaxation at the end of pregnancy. While leukocytes may accurately reflect changes in myometrial $\beta$-adrenoceptors, postreceptor differences suggest that they are not a reasonable indicator of myometrial response to $\beta$-AR stimulation.

Document Type

Dissertation - unrestricted

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