Gonadal steroids regulate adrenergic myometrial contractility in many species including humans. Regulation is similar in humans and rabbits, a useful model to examine the mechanisms of hormonal regulation. In estrogen primed progesterone treated (E2-P4) rabbits response to sympathetic stimulation is inhibition of contraction mediated by Beta-2 receptors. Ovariectomized (ovx.), mature or estrogen treated (E2) animals respond to the same stimulus with Alpha-1 mediated contraction. Estrogen further modifies Alpha-1 response with sensitivity greater in mature or E2 than in ovx. animals. Although sex steroids modify concentrations of adrenergic receptors these changes cannot explain the progesterone induced Beta-2 response or estrogen increased Alpha-1 sensitivity. In the beta responsive uterus of E2-P4 rabbits Alpha and Beta-receptor concentration and affinity are similar to those in ovx. (Alpha-1 response) rabbits. Increased Alpha-1 sensitivity with estrogen persists after receptor concentration decreases when estrogen is withdrawn. The modification of adrenergic response is best explained by hormonal effects beyond the receptor. Changes most likely are events close to the receptor since estrogen does not increase muscarinic sensitivity. We propose to study postreceptor regulation of Alpha-1 and Beta-adrenergic responses, as a novel mechanism for sex steroids. Beta receptor occupancy generates cAMP by interaction with a transducing protein, Gs. We found increased Gs in myometrium from E2-P4 rabbits. We will determine the role of increased Gs in the increased cAMP generation in these animals and if regulation also occurs at more distal sites (kinase-A or its substrates). Alpha-1 occupancy activates phospholipase-C yielding diacylglycerols which increase sensitivity of kinase-C (PKC) to Ca++ and polyphosphorylated inositol (IP3) which releases Ca++ from intracellular stores. We find estrogen increases Alpha-1 IP3 generation in myometrium. The mechanism for this effect and the role of PKC and its substrate will be determined. The uterus contains all adrenergic subtypes with their activity modified by sex steroids. Recent information indicates proximate interactions of postreceptor events. Steroid effects on one subtype could effect proximal responses to others since endogenous agonists, epinephrine and norepinephrine, interact with all subtypes. We will study the effects of simultaneous vs. isolated occupancy of receptor subtypes. Our studies provide insights into the control of uterine contractilty which we hope will suggest innovative approaches to stimulation and inhibition of uterine contractility.
