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 N G -nitro-L-arginine methyl ester (L-NAME, 50 mg/kg/day, oral gavage) to pregnant rats for 7 days starting from gestational day 14. Three therapies were co-administered orally with L-NAME, atrasentan (endothelin ETA receptor antagonist), terutroban (thromboxane A2 receptor antagonist, TXA2), or α-methyldopa (α-MD, 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-MD partially and similarly blunted the PE-evoked changes in CrCl and proteinuria, terutroban was the only drug that virtually abolished PE hypertension. Rises in cardiorenal inflammatory (tumor necrosis factor alpha, TNFα) and oxidative (isoprostane) markers were mostly and equally eliminated by all therapies in the two sexes, except for a greater dampening action of atrasentan, compared with α-MD, on tissue TNFα in female offspring only. Histopathologically, antenatal terutroban or atrasentan was more effective than α-MD in rectifying cardiac structural damage, myofiber separation, and cytoplasmic alterations, in PE offspring. 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-MD, the conventional PE therapy.

Preeclamptic programming unevenly perturbs inflammatory and renal vasodilatory outcomes of endotoxemia in rat offspring: modulation by losartan and pioglitazone

“…The female sex hormones have been implicated, at least in part, in the presumed favorable profile in the female compared with the male population ( Grigore et al, 2008 ; El-Lakany et al, 2018 ). Nonetheless, contradictory data of no sex differences or even worsened cardiovascular and metabolic outcomes in females than in males in the setting of PE ( Habib et al, 2021 ; Beckers et al, 2022 ; Kuciene and Dulskiene, 2022 ; Ushida et al, 2022 ) and sepsis ( Wedn et al, 2020 ; Fitzgerald et al, 2021 ) have been also recognized. Such discrepancies can be accounted for by differences in animal species, age, disease model, and specific biological activity under investigation.…”