Characterization of myometrial desensitization to β-adrenergic agonists

Abstract

Continuous exposure of ovine myometrial strips exposed to isoproterenol (10 microM) resulted in only transient inhibition with contractions returning within 60 min. Rechallenging these strips with isoproterenol failed to induce inhibition, confirming the occurrence of desensitization. In contrast, exposure of myometrial tissue to isoproterenol for only 5 min did not result in desensitization. Myometrial strips exposed to isoproterenol demonstrated a significant increase in cAMP content associated with inhibition of contractile activity and a subsequent fall in cAMP content upon desensitization. Elevation of endogenous cAMP levels by either inhibition of cAMP-dependent phosphodiesterase activity (0.5 mM isobutylmethylxanthine, in ovine strips) or direct activation of adenylyl cyclase (10 microM forskolin, in rat strips) induced a rapid and significant inhibition of myometrial contractile activity in desensitized tissue. Scatchard analysis of the binding of the beta-adrenoceptor antagonist, [125I]iodocyanopindolol, revealed a significant reduction in the concentration of beta-adrenergic receptors (but no change in binding affinity) in desensitized myometrial tissue. Incubation of desensitized tissue with fresh buffer for 3 h induced only a partial recovery in responsiveness to isoproterenol. These data suggest that prolonged, but not acute, exposure of the myometrium to beta-adrenergic agonists induces a state of desensitization that is associated with a down-regulation of beta-adrenoceptors but maintenance of postreceptor function.

The Initiation and Inhibition of Labor - Toward a Molecular Understanding

“…In contrast, we found that de sensitization was associated with a significant re duction in the number (but not affinity) of β-adren ergic receptors. 41 We have observed similar examples of homolo gous myometrial desensitization to β-adrenergic agonists in vivo in rats 43 as well as nonpregnant 44 and pregnant sheep. 45 In the latter study preterm labor was induced in sheep by injection of the pro gesterone receptor antagonist, RU486.…”

“…Administration of β-agonists in vitro produces only a transient inhibi tion of contractile activity with contractions return ing even though the myometrium remains exposed to active drug. 22,41,42 Coincident with this loss of responsiveness is a significant reduction in tissue cAMP levels and in β-agonist induced cAMP accu mulation. Postreceptor mechanisms remained func tional during homologous desensitization of the myometrium because elevation of endogenous cAMP levels by methods that bypass the β-receptor (e.g., inhibition of cAMP-dependent phosphodiesterase activity, direct activation of adenylyl cyclase, or ad dition of GTP analogues) induces a rapid and sig nificant inhibition of myometrial contractile activity in desensitized tissue.…”

The Regulation of Oxytocin Receptor Expression in Human Myometrial Monolayer Culture.

“…Mechanisms for such a desensitizing phenomenon at the level of receptors have recently been reported to be similar to that of ƒÀ-adrenergic receptors (ƒÀ-ARs) (Mahan et al, 1985;Dayes et al, 1990;Hausdorff et al, 1990 A reported experiment using uterine muscle strips revealed that OT-induced uterine contraction tended to become weaker 30-60 minutes after OT treatment (Eiler et al, 1989). In the present study, however, the total OTR concentration showed no change during the 30 minute period after the addition of OT.…”

Possible role of the protein kinase C/CPI‐17 pathway in the augmented contraction of human myometrium after gestation

“…Adrenergic β ‐agonists have been used for the management of preterm labor, as they are effective in suppressing uterine smooth muscle contraction. However, it has been argued that β ‐agonists are not always beneficial for the treatment of preterm labor because there is a downregulation of β ‐adrenergic receptors and/or an uncoupling of β ‐adrenergic receptor to adenylate cyclase via Gs in the patients ( Litime et al , 1989 ; Dayes & Lye, 1990). The present study in human materials suggests that the inhibition of PKC β may be a novel therapeutic strategy in the treatment of the preterm labor.…”