Antenatal betamethasone has a sex-dependent effect on the in vivo response to endothelin in adult sheep

作者：Lee Jeong Heon; Zhang Jie; Flores Lourdes; Rose James C; Massmann G Angela; Figueroa Jorge P^*

来源：American Journal of Physiology - Regulatory, Integrative and Comparative Physiology, 2013, 304(8): R581-R587.

DOI：10.1152/ajpregu.00579.2012

• betamethasone
• sheep
• endothelin
• FK-506 binding protein 12.6
• ryanodine channel
• vascular resistance

Lee J-H, Zhang J, Flores L, Rose JC, Massmann GA, Figueroa JP. Antenatal betamethasone has a sex-dependent effect on the in vivo response to endothelin in adult sheep. Am J Physiol Regul Integr Comp Physiol 304: R581-R587, 2013. First published February 13, 2013; doi: 10.1152/ajpregu.00579.2012.-Antenatal steroid administration is associated with multiple cardiometabolic alterations, including hypertension; however, the mechanisms underlying this phenomenon are unclear. The aim of the present study was to ascertain, in vivo, the contribution of the endothelin system to the development of hypertension in the adult offspring and the signaling pathway involved. Pregnant sheep were treated with two doses of betamethasone (n = 23) or vehicle (n = 22) at 80 days (similar to 0.55) gestation and allowed to deliver at term. Adult sheep were chronically instrumented under general anesthesia to place vascular catheters and a femoral artery flow probe. Blood pressure and flow were recorded continuously, and femoral artery vascular resistance was calculated before and during administration of endothelin 1 (ET-1). Selective blockers (dantrolene, BQ123, niacinamide) or saline were administered simultaneously. Betamethasone-exposed animals exhibited a significant elevation in mean blood pressure (female: 98 +/- 1.8 vs. 92 +/- 2.1; males: 97 +/- 3.4 vs. 90 +/- 2.3; mmHg; P %26lt; 0.05). ET-1 elicited a significant increase in blood pressure (F = 56.4; P %26lt; 0.001) and in vascular resistance (F = 44.3; P %26lt; 0.001) in all groups. A betamethasone effect in the vascular resistance response to ET-1 (F = 25.7; P %26lt; 0.001) was present in females only, and the effect was partially blunted by niacinamide (F = 6.6; P %26lt; 0.01). Combined administration of niacinamide and BQ123, as well as of dantrolene abolished the betamethasone effect on vascular resistance. No significant differences in mRNA expression of ETA or ETB in endothelial or smooth muscle cells of resistance-size arteries were observed. We conclude that the betamethasone effect on vascular resistance is mediated by an enhanced response to ET-1 through ETA receptor via the cyclic ADPR/ryanodine pathway.

• 出版日期2013-4