| Normal pregnancy: mechanisms underlying the paradox of a ouabain-resistant state with elevated endogenous ouabain, suppressed arterial sodium calcium exchange, and low blood pressure. | |
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MedLine Citation:
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PMID: 22245773 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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). |
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Authors:
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Brandiese E Jacobs; Yong Liu; Maria V Pulina; Vera A Golovina; John M Hamlyn |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, P.H.S. Date: 2012-01-13 |
Journal Detail:
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Title: American journal of physiology. Heart and circulatory physiology Volume: 302 ISSN: 1522-1539 ISO Abbreviation: Am. J. Physiol. Heart Circ. Physiol. Publication Date: 2012 Mar |
Date Detail:
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Created Date: 2012-03-16 Completed Date: 2012-05-07 Revised Date: 2012-05-23 |
Medline Journal Info:
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Nlm Unique ID: 100901228 Medline TA: Am J Physiol Heart Circ Physiol Country: United States |
Other Details:
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Languages: eng Pagination: H1317-29 Citation Subset: IM |
Affiliation:
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Department of Physiology, School of Medicine, University of Maryland, Baltimore, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adrenal Glands
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metabolism Animals Arteries / drug effects*, metabolism* Blood Pressure / drug effects* Calcium / metabolism Cardenolides / blood, metabolism Cardiotonic Agents / administration & dosage*, toxicity Chromatography, Liquid Down-Regulation Drug Resistance* Female Fetal Growth Retardation / chemically induced Homeostasis Infusions, Subcutaneous Mass Spectrometry Ouabain / administration & dosage*, toxicity Peptides, Cyclic Placenta / drug effects, growth & development Pregnancy Radioimmunoassay Rats Rats, Sprague-Dawley Saponins / blood, metabolism Sodium-Calcium Exchanger / metabolism* TRPC Cation Channels / metabolism Time Factors Up-Regulation |
| Grant Support | |
ID/Acronym/Agency:
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HL-045215/HL/NHLBI NIH HHS; HL-078870/HL/NHLBI NIH HHS; HL-75584/HL/NHLBI NIH HHS; R25-GM55036/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Cardenolides; 0/Cardiotonic Agents; 0/Peptides, Cyclic; 0/Saponins; 0/Sodium-Calcium Exchanger; 0/TRPC Cation Channels; 0/TRPC3 cation channel; 0/TrPepz; 0/Trpc6 protein, rat; 0/digoxin-like factors; 0/sodium-calcium exchanger 1; 630-60-4/Ouabain; 7440-70-2/Calcium |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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