title: Normal pregnancy: mechanisms underlying the paradox of a ouabain-resistant state with elevated endogenous ouabain, suppressed arterial sodium calcium exchange, and low blood pressure.
abstract: Endogenous cardiotonic steroids (CTS) raise blood pressure (BP) via vascular sodium calcium exchange (NCX1.3) and transient receptor-operated channels (TRPCs). Circulating CTS are superelevated in pregnancy-induced hypertension and preeclampsia. However, their significance in normal pregnancy, where BP is low, is paradoxical. Here we test the hypothesis that vascular resistance to endogenous ouabain (EO) develops in normal pregnancy and is mediated by reduced expression of NCX1.3 and TRPCs. We determined plasma and adrenal levels of EO and the impact of exogenous ouabain in pregnancy on arterial expression of Na(+) pumps, NCX1.3, TRPC3, and TRPC6 and BP. Pregnant (embryonic day 4) and nonpregnant rats received infusions of ouabain or vehicle. At 14-16 days, tissues and plasma were collected for blotting and EO assay by radioimmunoassay (RIA), liquid chromatography (LC)-RIA, and LC-multidimensional mass spectrometry (MS3). BP (-8 mmHg; P < 0.05) and NCX1.3 expression fell (aorta -60% and mesenteric artery -30%; P < 0.001) in pregnancy while TRPC expression was unchanged. Circulating EO increased (1.14 ± 0.13 nM) vs. nonpregnant (0.6 ± 0.08 nM; P < 0.05) and was confirmed by LC-MS3 and LC-RIA. LC-MS3 revealed two previously unknown isomers of EO; one increased ∼90-fold in pregnancy. Adrenal EO but not isomers were increased in pregnancy. In nonpregnant rats, similar infusions of ouabain raised BP (+24 ± 3 mmHg; P < 0.001). In ouabain-infused rats, impaired fetal and placental growth occurred with no BP increase. In summary, normal pregnancy is an ouabain-resistant state associated with low BP, elevated circulating levels of EO, two novel steroidal EO isomers, and increased adrenal mass and EO content. Ouabain raises BP only in nonpregnant animals. Vascular resistance to the chronic pressor activity of endogenous and exogenous ouabain is mediated by suppressed NCX1.3 and reduced sensitivity of events downstream of Ca(2+) entry. The mechanisms of EO resistance and the impaired fetal and placental growth due to elevated ouabain may be important in pregnancy-induced hypertension (PIH) and preeclampsia (PE).
authors.affiliation: Department of Physiology, School of Medicine, University of Maryland, Baltimore, USA.
authors.forename: Brandiese E
authors.initials: BE
authors.lastname: Jacobs
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.forename: Maria V
authors.initials: MV
authors.lastname: Pulina
authors.forename: Vera A
authors.initials: VA
authors.lastname: Golovina
authors.forename: John M
authors.initials: JM
authors.lastname: Hamlyn
mesh_terms: D000311:Adrenal Glands / Q000378:metabolism; D000818:Animals; D001158:Arteries / Q000187:drug effects* / Q000378:metabolism*; D001794:Blood Pressure / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D002298:Cardenolides / Q000097:blood / Q000378:metabolism; D002316:Cardiotonic Agents / Q000008:administration & dosage* / Q000633:toxicity; D002853:Chromatography, Liquid; D015536:Down-Regulation; D004351:Drug Resistance; D005260:Female; D005317:Fetal Growth Retardation / Q000139:chemically induced; D006706:Homeostasis; D055104:Infusions, Subcutaneous; D013058:Mass Spectrometry; D010042:Ouabain / Q000008:administration & dosage* / Q000633:toxicity; D010456:Peptides, Cyclic; D010920:Placenta / Q000187:drug effects; D010929:Placentation; D011247:Pregnancy; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D012503:Saponins / Q000097:blood / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism*; D050052:TRPC Cation Channels / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D002298:Cardenolides; D002316:Cardiotonic Agents; D010456:Peptides, Cyclic; D012503:Saponins; D019831:Sodium-Calcium Exchanger; D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; C087265:TrPepz; C492145:Trpc6 protein, rat; C034504:digoxin-like factors; C110374:sodium-calcium exchanger 1; D010042:Ouabain; D002118:Calcium