Antenatal betamethasone increases vascular reactivity to endothelin-1 by upregulation of CD38/cADPR signaling.
Antenatal steroid administration is associated with hypertension in adult life; however, the mechanisms underlying this phenomenon are unclear. The aim of this study was to further characterize the effects of antenatal glucocorticoid exposure on the endothelin (ET-1) system, specifically to ascertain the role of the cyclic adenosine diphosphate ribose (cADPR)/ryanodine receptor pathway in the increased sensitivity to ET-1 observed in the offspring exposed to antenatal glucocorticoids. Pregnant sheep were randomly treated with betamethasone (Beta; 0.17 mg/kg) or vehicle at 80 and 81 days of gestation. In adults, we studied endothelium-denuded arterial segments of the brachial arteries. ET-1-induced vasoconstriction was significantly higher in the arteries from Beta sheep (F=3.5, P<0.05). Inhibition of ADP-ribosyl cyclase with 2-2'-dihydroxy-azobenzene significantly decreased the ET-1-induced contraction in Beta but not in vehicle-treated sheep. Nicotinamide attenuated ET-1 contraction in both, but it was significantly more pronounced in the Beta-treated sheep. No significant differences were observed following KCl-induced (6.25-75 mM) contraction. Nicotinamide (10 mM) significantly attenuated the KCl-induced vasoconstriction in both groups. In KCl (62.5 mM)-constricted arteries, the effect of nicotinamide (NIC) was significantly greater in the vehicle-treated sheep (50% relaxation v. 40% relaxation; t=2.2, P<0.05). In contrast, the sodium nitroprusside (SNP) relaxation was not statistically different. An additive effect was observed when NIC and SNP were used in combination and it was also more pronounced in vehicle-treated sheep. We conclude that the increased response to ET-1 is mediated by activation of the CD38/cADPR signaling pathway. Further studies are required to identify the effectors downstream from cADPR affected by exposure to antenatal steroids.
1 Department of Obstetrics and Gynecology, Center for Research in Obstetrics and Gynecology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
J-H
JH
Lee
1 Department of Obstetrics and Gynecology, Center for Research in Obstetrics and Gynecology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
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J
Zhang
1 Department of Obstetrics and Gynecology, Center for Research in Obstetrics and Gynecology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
G A
GA
Massmann
1 Department of Obstetrics and Gynecology, Center for Research in Obstetrics and Gynecology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
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JP
Figueroa
D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism*; D000818:Animals; D001623:Betamethasone / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D036563:Cyclic ADP-Ribose / Q000378:metabolism*; D019332:Endothelin-1 / Q000494:pharmacology*; D005260:Female; D009536:Niacinamide / Q000494:pharmacology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012756:Sheep; D015398:Signal Transduction; D015854:Up-Regulation
D019332:Endothelin-1; D036563:Cyclic ADP-Ribose; D009536:Niacinamide; D001623:Betamethasone; D051997:ADP-ribosyl Cyclase 1