- 作者：Robyn P. Roberts ; MD ; robyn.p.roberts@uth.tmc.edu" class="auth_mail" title="E-mail the corresponding author ; Jerrie S. Refuerzo ; MD ; Francesca Ferrari ; MD ; Alejandra E. Ontiveros ; MD ; Esther H. Tamayo ; Baha M. Sibai ; MD ; Sean C. Blackwell ; MD ; Monica Longo ; MD ; PhD
- 关键词：endothelial nitric oxide synthase ; hypertension ; pregnancy ; sildenafil
- 刊名：American Journal of Obstetrics and Gynecology
- 出版年：2016
- 出版时间：September 2016
- 年：2016
- 卷：215
- 期：3
- 页码：386.e1-386.e8
- 全文大小：1118 K
Objective
The objective of the study was to determine whether treatment with sildenafil during pregnancy would lower maternal systolic blood pressure without adversely affecting fetal growth.
Study Design
Females with nonsevere hypertension (endothelial nitric oxide synthase+/–) were cross-bred with normotensive wild-type males. At gestational day 1, pregnant dams were randomized to either sildenafil (0.4 mg/mL per day, comparable dose used in human pregnancy) or water for 3 weeks. Four groups were then generated: wild type (n = 7), wild type-sildenafil (n = 11), endothelial nitric oxide synthase+/– (n = 8), and endothelial nitric oxide synthase+/–sildenafil (n = 7). On gestational day 18, systolic blood pressure was measured. Dams were killed, fetal and placental weights were obtained, and carotid arteries were dissected to measure in vitro vascular reactivity with a wire-myography system. Responses to phenylephrine, L-NG-nitroarginine methyl ester, acetylcholine, and sodium nitroprusside were studied.
Results
Mean systolic blood pressure was elevated in the endothelial nitric oxide synthase+/– dams compared with wild-type controls (P = .03). Treatment with sildenafil decreased systolic blood pressure in the endothelial nitric oxide synthase+/––treated dams compared with nontreated endothelial nitric oxide synthase+/– dams (P = .03). No differences were seen in the wild-type dams with or without sildenafil (P = .47). Fetuses from endothelial nitric oxide synthase+/– dams were smaller compared with wild-type controls (P < .001); however, when these endothelial nitric oxide synthase+/– dams were treated with sildenafil, fetal weight increased compared with the nontreated endothelial nitric oxide synthase+/– group (P < .001). No difference were seen in wild-type groups treated or not treated with sildenafil (P = .41). Placental weights were not significantly different among groups (endothelial nitric oxide synthase+/–sildenafil vs endothelial nitric oxide synthase+/– [P = .48]; wild-type-sildenafil vs wild type [P = .52]). Maximal vascular contraction induced by phenylephrine was blunted in endothelial nitric oxide synthase+/– dams treated with sildenafil compared with nontreated endothelial nitric oxide synthase+/– dams (P < .01). No change in contractile response was seen in wild-type groups treated or not treated (P = .53). When vessels were preincubated with L-NG-nitroarginine methyl ester, the contractile responses were similar among all groups (P = .54). In addition, maximal vascular relaxation induced by acetylcholine was improved in the endothelial nitric oxide synthase+/– dams treated with sildenafil compared with endothelial nitric oxide synthase+/– nontreated dams (P < .01). No change in relaxation response was seen in wild-type groups treated or not treated (P = .62). Sodium nitroprusside did not change the contractile response in any of the groups (P = .31).
Conclusion
Pregnant dams deficient in endothelial nitric oxide synthase, a nonsevere hypertensive murine model, treated with sildenafil had lower maternal systolic blood pressure, increased fetal growth, and improvement in vascular reactivity. Treatment with sildenafil may be beneficial in pregnancies complicated by nonsevere hypertension.