Modulation by Antenatal Therapies of Cardiovascular and Renal Programming in Male and Female Offspring of Preeclamptic Rats

Abstract

Morbidity and mortality risks are enhanced in preeclamptic (PE) mothers and their offspring. Here we asked if sexual dimorphism exists in (i) cardiovascular and renal damage evolved in offspring of PE mothers, and (ii) offspring responsiveness to antenatal therapies. PE was induced by administering NAME (50 mg/kg/day, oral gavage) to pregnant rats for 7 days starting from gestational day 14. Three therapies were co-administered with L-NAME, atrasentan (ETA receptor blocker), terutroban (TXA2 receptor blocker), or α-methyldopa (central sympatholytic drug). Cardiovascular and renal profiles were assessed in 3-month-old offspring. Compared with offspring of non-PE rats, PE offspring exhibited elevated systolic blood pressure and proteinuria and reduced heart rate and creatinine clearance (CrCl). Apart from a greater bradycardia in male offspring, similar PE effects were noted in male and female offspring. While terutroban, atrasentan, or α-methyldopa partially and similarly blunted the PE-evoked changes in CrCl and proteinuria, terutroban was the only drug that virtually abolished PE hypertension. Rises in inflammatory (TNFα) and oxidative (isoprostane) markers in cardiac and renal tissues of PE offspring were mostly and equally eliminated by all therapies in the two sexes, except for a greater dampening action of atrasentan, compared with α-methyldopa, on tissue TNFα in female offspring only. Histopathologically, antenatal terutroban or atrasentan was more effective than α-methyldopa in rectifying cardiac structural damage, myofiber separation and cytoplasmic alterations, in PE offspring. Overall, the repair by antenatal terutroban or atrasentan of cardiovascular and renal anomalies in PE offspring is mostly sex-independent and surpasses the protection offered by α-methyldopa, the conventional PE therapy.