Intrapartum Sildenafil Therapy Reprograms Susceptibility to Hypertension in Offspring of Dahl S Rats
Authors: Turbeville Hannah R , Desai Aalaap , Garrett Michael R , Sasser Jennifer M 
Published: June 2021

Up to 15 million people in the United States are offspring of preeclamptic pregnancies. These offspring have increased blood pressure (BP) during childhood as well as nearly double the risk of stroke later in life. The Developmental Origins of Health and Disease (DOHAD) hypothesis proposes that the adverse intrauterine environment created by preeclampsia programs fetal tissues and organs to develop high BP from early childhood. Sildenafil citrate (SLD, a PDE‐5 inhibitor) improves the maternal syndrome of preeclampsia in the Dahl S rat, and we have shown that offspring of dams treated with SLD during gestation exhibit significantly decreased systolic BP at 11 weeks of age compared to age‐matched offspring of vehicle‐fed dams. The objective of this study was to test the hypothesis that intrapartum SLD would attenuate the BP programming effects on offspring of preeclamptic pregnancies in this model. Female Dahl S rats on a 0.3% salt diet, a previously characterized spontaneous model of superimposed preeclampsia, were mated and treated orally with SLD (50 mg/kg/day), labetalol (LAB, currently used to manage hypertension in preeclamptic patients, 10 mg/kg/day), or vehicle (VEH) from gestational day 10 to delivery. Dams were placed on normal rat chow at delivery throughout weaning at four weeks of age. To determine if SLD could attenuate the susceptibility to hypertensive stimuli, groups of offspring were exposed to one of two secondary hits: high‐salt diet (2% NaCl, Harlan Teklad, four weeks), or subpressor angiotensin II infusion (200 ng/kg/min, Alzet 2002 pump, two weeks). In both experiments, rats were implanted with telemetry devices (DSI, HD‐S10) via the femoral artery at ten weeks of age and allowed to recover for ten days before administration of high‐salt diet ad libitum or implantation of osmotic minipumps containing angiotensin II. On a high‐salt diet, mean arterial pressure (MAP) increased in all animals as expected; however, male offspring of SLD‐treated dams exhibited a significant attenuation of this increase after four weeks high salt (n=3–7/group). Although female offspring show no differences between groups, this could be due to a lower number of animals present in the female VEH group. On exposure to angiotensin II, all animals exhibited an increase in MAP (n=4/group), with a smaller rise in females as expected. No difference was seen between female groups by study completion. However, male offspring of SLD‐treated dams exhibited a significantly lower plateau than did male offspring of VEH‐fed or LAB‐treated dams. These data indicate that sildenafil citrate not only improves the maternal phenotype of superimposed preeclampsia in the Dahl S rat, but also acts to reprogram hypertension and response to secondary hits in the offspring of preeclamptic pregnancies.

Support or Funding Information

This work was supported by the National Institutes of Health (F30DK118864 [HRT], R01HL137673 [MRG], and R01HL134711 [JMS]).

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.