Myometrial angiotensin II receptor subtypes change during ovine pregnancy

Although regulation of angiotensin II receptor (AT) binding in vascular and uterine smooth muscle is similar in nonpregnant animals, studies suggest it may differ during pregnancy. We, therefore, examined binding characteristics of myometrial AT receptors in nulliparous (n = 7), pregnant (n = 24, 110-139 d of gestation), and postpartum (n = 21,5 to ≥ 130 d) sheep and compared this to vascular receptor binding. We also determined if changes in myometrial binding reflect alterations in receptor subtype. By using plasma membrane preparations from myometrium and medial layer of abdominal aorta, we determined receptor density and affinity employing radioligand binding; myometrial AT receptor subtypes were assessed by inhibiting [¹²⁵I)-ANG II binding with subtype-specific antagonists. Compared to nulliparous ewes, myometrial AT receptor density fell ∼ 90% during pregnancy (1,486±167 vs. 130±16 fmol/mg protein) and returned to nulliparous values ≥ 4 wk postpartum; vascular binding was unchanged. Nulliparous myometrium expressed predominantly AT₂ receptors (AT₁/AT₂ ≃ 15%/85%), whereas AT₁ receptors predominated during pregnancy (AT₁/AT₂ ≃ 80%/20%). By 5 d postpartum AT₁/AT₂ ≃ 40%/60%, and > 4 wk postpartum AT₂ receptors again predominated (AT₁/AT₂ ≃ 15%/85%). In studies of ANG II-induced force generation, myometrium from pregnant ewes (n = 10) demonstrated dose-dependent increases in force (P < 0.001), which were inhibited with an AT, receptor antagonist. Postpartum myometrial responses were less at doses ≥ 10^-9 M (P < 0.05) and unaffected by AT₂ receptor antagonists. Vascular and myometrial AT receptor binding are differentially regulated during ovine pregnancy, the latter primarily reflecting decreases in AT₂ receptor expression. This is the first description of reversible changes in AT receptor subtype in adult mammals.