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Modulation by antenatal therapies of cardiovascular and renal programming in male and female offspring of preeclamptic rats

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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 NG-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.

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Authors and Affiliations

  1. Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Pharos University in Alexandria, Alexandria, Egypt

    Yasser H. Habib, Mennatallah A. Gowayed, Sherien A. Abdelhady & Inas E. Darwish

  2. Department of Clinical Pathology, Faculty of Medicine, Alexandria University, Alexandria, Egypt

    Nevine M. El-Deeb

  3. Department of Clinical Pharmacology, Faculty of Medicine, Alexandria University, Alexandria, Egypt

    Inas E. Darwish

  4. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt

    Mahmoud M. El-Mas

  5. Department of Pharmacology and Toxicology, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait

    Mahmoud M. El-Mas

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Contributions

ID and ME conceived and designed research. YH, MG, SA, and NE conducted experiments. MG, SA, and NE contributed new reagents or analytical tools. YH, MG, SA, and NE analyzed data. MG, SA, and ME wrote the manuscript. All authors read and approved the manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

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Correspondence to Mahmoud M. El-Mas.

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All the animal manipulations and care were performed in accordance with the “National Research Council’s Guide for the Care and Use of Laboratory Animals” (SR and G 2016) and Unit of Research Ethics Approval Committee, Pharos University in Alexandria, Egypt (Approval No.: 01201903031005) and with ARRIVE guidelines and the National Institutes of Health, USA, for the care and use of laboratory animals.

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Habib, Y.H., Gowayed, M.A., Abdelhady, S.A. et al. Modulation by antenatal therapies of cardiovascular and renal programming in male and female offspring of preeclamptic rats. Naunyn-Schmiedeberg's Arch Pharmacol 394, 2273–2287 (2021). https://doi.org/10.1007/s00210-021-02146-7

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