Angiotensin receptor subtypes in the uterine artery during ovine pregnancy

Abstract

This study was undertaken to determine if changes in receptor density or affinity could account for the reduced vascular sensitivity to angiotensin II seen during pregnancy. Angiotensin receptor subtypes in the uterine arteries of non-pregnant, pregnant and postpartum ewes were investigated using saturation and competition receptor binding techniques with the specific receptor antagonists, losartan (DuP-753) and PD-123319 ( S)1-[[4-(dimethylamino)-3-methylphenyl]-methyl]-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1 H-imidazo(4,5- c)pyridine-6-carboxylic acid, ditrifluoroacetate, monohydrate). Receptor density and affinity of total angiotensin receptors, as well as the angiotensin AT 1 and AT 2 receptor subtypes in uterine arteries were compared with those in the mesenteric artery and aorta. The uterine artery contains both AT 1 and AT 2 receptor subtypes, whereas the mesenteric artery and aorta contain primarily the AT 1 receptor subtype. In uterine arteries from pregnant sheep, angiotensin receptor density was increased because AT 2 receptors were increased. AT 1 receptor density was not altered. This change was not seen in the aorta. In the uterine artery, receptor affinity for [Sar 1,Ile 8]angiotensin II decreased in mid-gestation (IC 50 7.7±1.2×10 −9 M) compared with non-pregnant ewes (IC 50 3.0±0.6×10 −9 M, P=0.006), and there was decreased affinity of angiotensin AT 1 receptors for losartan during pregnancy (IC 50 2.8±1.0×10 −4 M) compared with non-pregnant ewes (IC 50 2.2±1.3×10 −6 M, P=0.025). Our results show changes in the density and affinity of the angiotensin receptor subtypes in the uterine artery which could explain its reduced responsiveness to circulating angiotensin II during pregnancy.