In-vitro study of the effect of anti-hypertensive drugs on placental hormones and angiogenic proteins synthesis in pre-eclampsia.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science

Angiogenic Proteins/*metabolism ; Antihypertensive Agents/*pharmacology ; Placenta/*drug effects ; Placental Hormones/*metabolism; Activins/metabolism ; Antigens, CD/metabolism ; Chorionic Gonadotropin/metabolism ; Chorionic Villi/drug effects ; Chorionic Villi/metabolism ; Dose-Response Relationship, Drug ; Endoglin ; Enzyme-Linked Immunosorbent Assay ; Female ; Humans ; Hydralazine/pharmacology ; Labetalol/pharmacology ; Methyldopa/pharmacology ; Placenta/metabolism ; Pravastatin/pharmacology ; Pre-Eclampsia/drug therapy ; Pre-Eclampsia/metabolism ; Pregnancy ; Receptors, Cell Surface/metabolism ; Time Factors ; Tissue Culture Techniques ; Vascular Endothelial Growth Factor Receptor-1/metabolism

Introduction: Antihypertensive drugs lower the maternal blood pressure in pre-eclampsia (PE) by direct or central vasodilatory mechanisms but little is known about the direct effects of these drugs on placental functions.
Objective: The aim of our study is to evaluate the effect of labetolol, hydralazine, α-methyldopa and pravastatin on the synthesis of placental hormonal and angiogenic proteins know to be altered in PE.
Design: Placental villous explants from late onset PE (n = 3) and normotensive controls (n = 6) were cultured for 3 days at 10 and 20% oxygen (O2) with variable doses anti-hypertensive drugs. The levels of activin A, inhibin A, human Chorionic Gonadotrophin (hCG), soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng) were measured in explant culture media on day 1, 2 and 3 using standard immunoassays. Data at day 1 and day 3 were compared.
Results: Spontaneous secretion of sEndoglin and sFlt-1 were higher (p < 0.05) in villous explants from PE pregnancies compared to controls. There was a significant time dependent decrease in the secretion of sFlt-1 and sEndoglin in PE cases, which was seen only for sFlt-1 in controls. In both PE cases and controls the placental protein secretions were not affected by varying doses of anti-hypertensive drugs or the different O2 concentration cultures, except for Activin, A which was significantly (p < 0.05) higher in controls at 10% O2.
Interpretation: Our findings suggest that the changes previously observed in maternal serum hormones and angiogenic proteins level after anti-hypertensive treatment in PE could be due to a systemic effect of the drugs on maternal blood pressure and circulation rather than a direct effect of these drugs on placental biosynthesis and/or secretion.

Hypertens Pregnancy. 2001;20(1):IX-XIV. (PMID: 12044323)
Am J Obstet Gynecol. 2012 Oct;207(4):337.e1-8. (PMID: 23021701)
J Clin Endocrinol Metab. 1998 May;83(5):1697-705. (PMID: 9589679)
Placenta. 2011 Feb;32 Suppl:S49-54. (PMID: 21257083)
J Auton Nerv Syst. 1998 Oct 15;72(2-3):163-9. (PMID: 9851565)
Placenta. 2012 Feb;33 Suppl:S81-6. (PMID: 22138060)
PLoS One. 2008 Jul 23;3(7):e2766. (PMID: 18648513)
Hum Reprod Update. 2006 Nov-Dec;12(6):747-55. (PMID: 16682385)
Clin Exp Pharmacol Physiol. 1994 Aug;21(8):615-22. (PMID: 7529152)
J Matern Fetal Neonatal Med. 2013 Aug;26(12):1228-33. (PMID: 23413799)
Methods Mol Med. 2006;122:413-25. (PMID: 16511998)
Adv Chronic Kidney Dis. 2013 May;20(3):229-39. (PMID: 23928387)
N Engl J Med. 1993 Oct 21;329(17):1213-8. (PMID: 8413387)
J Matern Fetal Neonatal Med. 2013 Mar;26(5):491-6. (PMID: 23035823)
Drugs. 2012 Mar 5;72(4):565-84. (PMID: 22356292)
J Hypertens. 2006 May;24(5):915-22. (PMID: 16612254)
Acta Obstet Gynecol Scand. 2012 Dec;91(12):1388-94. (PMID: 22882089)
J Clin Endocrinol Metab. 2012 Aug;97(8):E1370-9. (PMID: 22685232)
Placenta. 2012 Feb;33 Suppl:S42-7. (PMID: 22197626)
Cytokine. 2009 Jul;47(1):56-60. (PMID: 19501525)
Am J Pathol. 2011 Mar;178(3):1177-89. (PMID: 21356369)
Am J Pathol. 2004 Mar;164(3):1049-61. (PMID: 14982858)
J Clin Endocrinol Metab. 1996 Sep;81(9):3328-34. (PMID: 8784092)
BJOG. 2012 Jun;119(7):778-87. (PMID: 22433027)
Am J Pathol. 2000 Dec;157(6):2111-22. (PMID: 11106583)
Am J Pathol. 2001 Sep;159(3):1031-43. (PMID: 11549595)
J Clin Hypertens (Greenwich). 2011 Sep;13(9):690-2. (PMID: 21896152)
PLoS One. 2008 Jun 04;3(6):e2302. (PMID: 18523681)
Best Pract Res Clin Obstet Gynaecol. 2011 Jun;25(3):301-11. (PMID: 21109492)
Reprod Biomed Online. 2004 Jun;8(6):712-9. (PMID: 15169590)
PLoS One. 2009;4(2):e4453. (PMID: 19412349)
Am J Pathol. 2003 Jan;162(1):115-25. (PMID: 12507895)
J Recept Res. 1994 May;14(3-4):187-95. (PMID: 8083863)
Best Pract Res Clin Obstet Gynaecol. 2011 Jun;25(3):273-85. (PMID: 21212025)
Pharmgenomics Pers Med. 2012;5:37-51. (PMID: 23226061)
Am J Obstet Gynecol. 2011 Mar;204(3):193-201. (PMID: 21094932)
Placenta. 2005 Jan;26(1):53-8. (PMID: 15664411)
Placenta. 2012 Feb;33 Suppl:S48-54. (PMID: 22217911)
Obstet Gynecol. 2013 Feb;121(2 Pt 1):349-353. (PMID: 23344286)
Ann N Y Acad Sci. 1999 Jun 21;881:279-86. (PMID: 10415926)
Clin Endocrinol (Oxf). 2009 Jun;70(6):924-31. (PMID: 18803676)
Clin Exp Pharmacol Physiol. 2009 Aug;36(8):839-42. (PMID: 19215236)
Cardiol Clin. 2012 Aug;30(3):407-23. (PMID: 22813366)
Am J Pathol. 2007 Oct;171(4):1168-79. (PMID: 17823277)
Eur J Endocrinol. 2005 Jun;152(6):909-16. (PMID: 15941932)

0 (Angiogenic Proteins)
0 (Antigens, CD)
0 (Antihypertensive Agents)
0 (Chorionic Gonadotropin)
0 (ENG protein, human)
0 (Endoglin)
0 (Placental Hormones)
0 (Receptors, Cell Surface)
0 (activin A)
104625-48-1 (Activins)
26NAK24LS8 (Hydralazine)
56LH93261Y (Methyldopa)
EC 2.7.10.1 (FLT1 protein, human)
EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-1)
KXO2KT9N0G (Pravastatin)
R5H8897N95 (Labetalol)

Date Created: 20140925 Date Completed: 20150623 Latest Revision: 20220331

20240513

PMC4175458

10.1371/journal.pone.0107644

25251016