Ritodrine, a Beta2-adrenergic agonist, is widely used for suppression of premature labor. Ritodrine presumably mediates myometrial relaxation as well as many of its reported side effects such as tachycardia, hypertension, and changes in glucose metabolism through the B-adrenergic receptor effector cascade system, including the B-receptor, coupling protein, adenylate cyclase/cAMP and cAMP-dependent protein kinase. Ritodrine-induced tissue desensitization (tachyphylaxis) of the receptor-cyclase system may be a major determinate of the drug's physiological effects. The requirement for tissue samples from the mother or fetus normally makes study of drug tachyphylaxis in pregnancy difficult. Two readily available tissues, the placenta and the fetal membranes contain B-adrenergic receptor effector cascade systems, however. Further, catecholamines and cAMP appear to modulate estrogen and progesterone production in the placenta and prostaglandin production in the amnion. In addition, ritodrine lowers serum estrogen, progesterone and prostaglandin levels. Placenta and amnion thus provide available models for the study of ritodrine-induced tachyphylaxis. This proposal will test the hypothesis that ritodrine induces tachyphylaxis of the B-adrenergic effector cascade systems in human placenta and amnion which thereby inhibit catecholamine-stimulated increases in estrogen and progesterone production by the placenta, and prostaglandin production by the amnion. Trophoblastic cells, placental explants and amniotic membrane punches from term and preterm gestation placentae will be exposed to ritodrine in vitro following which differences in each component of the B-adrenergic effector cascade (listed above) and changes in catecholamine-stimulated estrogen and progesterone (placenta) or prostaglandin (amnion) production will be determined. Similarly, differences in placentas exposed to ritodrine under clinical conditions (in vivo) will be compared with controls of similar gestation. The results of this study should provide information concerning the capability of ritodrine, as used under clinical conditions, to regulate the sensitivity of B-adrenergic system and more clearly define the effect of catecholamines and B-adrenergic agents such as ritodrine upon the major hormones of pregnancy.
