Antihypertensive drugs clonidine, diazoxide, hydralazine and furosemide regulate the production of cytokines by placentas and peripheral blood mononuclear cells in normal pregnancy.
BACKGROUND
Antihypertensive drugs such as clonidine, diazoxide, hydralazine and furosemide are used in the hypertensive disorders of pregnancy to control blood pressure, but it is not clear if they modulate the production of placental or circulating cytokines.


OBJECTIVE
To examine the effect of pharmaceutical doses of well known antihypertensive drugs used for blood pressure control on the production of the cytokines interleukin (IL)-6, IL-10 and tumour necrosis factor (TNF)-alpha in placental tissue and peripheral blood mononuclear cells (PBMCs) in normal pregnancy.


METHODS
Placental biopsies were taken from the decidual surface of placentas after delivery of normal pregnancies (n = 6) and PBMCs were separated from the whole blood of normal term pregnant women (n = 7). Both villous explants and PBMCs were cultured with increasing concentrations of antihypertensive drugs. The dose effect of drugs on the production of placental and circulating cytokines (IL-6, IL-10 and TNF-alpha) were examined by enzyme-linked immunosorbent assay.


RESULTS
Placental production of IL-10 was not affected by clonidine, but decreased significantly after incubation of the tissue with diazoxide, hydralazine or furosemide. Production of IL-10 by PBMCs increased significantly: by from 3.4 +/- 2.7% [16.3 pg/ml (range 6.1-21.5 pg/ml)] to 24.5 +/- 3.3% [30.4 pg/ml (range 16.9-34.8 pg/ml)] with increasing concentrations of clonidine (0.08-1.3 microg/ml), and by 8.8 +/- 3.5% [4.1 pg/ml (range 3.0-17.8 pg/ml)] and 17.2 +/- 1.9% [22.6 pg/ml (range 13.2-23.2 pg/ml)] with lower doses of hydralazine (6.3 and 12.5 microg/ml) (all P values < 0.05). There was a stepwise reduction in production of TNF-alpha and IL-6 with increasing doses of diazoxide, hydralazine and furosemide by placentas and PBMCs from these women with normal pregnancies.


CONCLUSIONS
Our data suggest that the antihypertensive drugs clonidine and hydralazine can stimulate production of the circulating anti-inflammatory cytokine IL-10, whereas furosemide and diazoxide inhibit the production of this cytokine and the proinflammatory cytokines TNF-alpha and IL-6 by placentas and PBMCs.
Xu
Bei
B
Vascular Immunology Research Laboratory, The Heart Research Institute, University of Sydney, Australia. bei_xu2001@yahoo.com
Makris
Angela
A
Thornton
Charlene
C
Ogle
Robert
R
Horvath
John S
JS
Hennessy
Annemarie
A
D000959:Antihypertensive Agents / Q000494:pharmacology*; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D003000:Clonidine / Q000494:pharmacology; D017077:Culture Media, Conditioned / Q000032:analysis / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D003981:Diazoxide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005665:Furosemide / Q000494:pharmacology; D005865:Gestational Age; D005947:Glucose / Q000032:analysis / Q000378:metabolism; D006801:Humans; D006830:Hydralazine / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D009924:Organ Culture Techniques; D010920:Placenta / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000032:analysis / Q000378:metabolism; D011263:Pregnancy Trimester, Third
D000959:Antihypertensive Agents; D017077:Culture Media, Conditioned; D016207:Cytokines; D008070:Lipopolysaccharides; D011257:Pregnancy Proteins; D006830:Hydralazine; D005665:Furosemide; D005947:Glucose; D003000:Clonidine; D003981:Diazoxide