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The Β-adrenergic receptors present in inner and outer layers of human myometrium near term were characterized using the radioiodinated antagonist iodocyanopindolol (ICYP). In both layers ICYP binding is saturable, rapidly reversible, stereoselective, and appears to occur in a single class of sites with a K_D of 30 pmol/l. Adrenergic agonists compete for ICYP binding sites with an order of potency consistent with Β₂-adrenergic potencies: isoproterenol > epinephrine > > norepinephrine. Studies in which CGP 20712 A, a Β₁ adrenergic antagonist, competes for ICYP binding sites in human myometrium reveal that at least 65% of the Β-receptors present are Β₂-subtype, whatever the layer considered. At the 35th week of pregnancy, the density of Β-adrenergic receptors in the inner layer (15.2 fmol/mg of protein) is about 50% higher than in the outer layer. At term, the densities of Β-adrenergic receptors are reduced and exhibit the same values for both layers (5 fmol/mg of protein). These results indicate that the Β-adrenergic receptors in the two layers diminish during pregnancy and reach, at term, an equal and low level of density.

The density of beta-adrenergic receptors in both the outer and inner layers of the human myometrium decreases during the last weeks of pregnancy. Although in preterm myometrium (32-35 weeks of pregnancy) beta-adrenergic receptors are positively coupled to adenylate cyclase, we found that isoproterenol, epinephrine, and norepinephrine did not stimulate the enzyme in the inner or outer myometrial layer at term (39-40 weeks of pregnancy). At this stage, the addition of 10(-4) mol/L guanyl-5'-imidodiphosphate increased (from 10(-8) to 10(-4) mol/L) basal adenylate cyclase activity in a dose-dependent manner, indicating that the catalytic component of the enzyme remains linked to the stimulatory guanyl nucleotide binding protein (Gs). Compared to the preterm response, at term the myometrial adenylate cyclase response to 10(-4) mol/L guanyl-5'-imidodiphosphate was decreased, which may reflect a decrease in the amount of functional Gs. Altogether these changes are consistent with reduced Gs coupling to the catalytic component. However, the similarity of the responses of preterm and term myometrium to forskolin excluded the possibility of an alteration of the catalytic component of adenylate cyclase during the last weeks of pregnancy. The fact that a stimulatory effect of isoproterenol on adenylate cyclase was found after islet-activating protein pretreatment indicates that human term myometrium contains a functional inhibitory guanyl nucleotide binding protein which is involved in the modulation of the beta-adrenergic adenylate cyclase response. Our data suggest that modifications in the coupling mechanisms between receptors and the catalytic component are implicated in the loss of beta-adrenergic adenylate cyclase stimulation in the myometrium at the end of pregnancy.

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