Assessment of Pregabalin-Induced Cardiotoxicity in Rats: Mechanistic Role of Angiotensin 1–7

  • Zeinab M. AwwadEmail author
  • Samar O. El-Ganainy
  • Ahmed I. ElMallah
  • Shaimaa M. Khedr
  • Mahmoud M. Khattab
  • Aiman S. El-Khatib


Pregabalin (PRG) possesses great therapeutic benefits in the treatment of epilepsy, neuropathic pain, and fibromyalgia. However, clinical data have reported incidence or exacerbation of heart failure following PRG administration. Experimental data exploring cardiac alterations and its underlying mechanisms are quite scarce. The aim of the present work was to investigate the effect of PRG on morphometric, echocardiographic, neurohumoral, and histopathological parameters in rats. It was hypothesized that alterations in cardiac renin angiotensin system (RAS) might be involved in PRG-induced cardiotoxicity. To further emphasize the role of RAS in the mechanism of PRG-induced cardiotoxicity, the protective potential of diminazene aceturate (DIZE), an ACE2 activator, was investigated. Results showed 44% decrease in ejection fraction and sevenfold increase in plasma N-terminal pro-brain natriuretic peptide. Histopathological examination also showed prominent vacuolar changes and edema in cardiomyocytes. In addition, PRG significantly increased angiotensin II (Ang II), angiotensin converting enzyme (ACE) and angiotensin II type 1 receptor (AT1R) levels, while decreased angiotensin 1–7 (Ang 1–7), angiotensin converting enzyme 2 (ACE2), and Mas receptor (MasR) cardiac levels. DIZE co-administration showed prominent protection against PRG-induced echocardiographic, neurohumoral, and histopathological alterations in rats. In addition, downregulation of ACE/Ang II/AT1R and upregulation of ACE2/Ang 1–7/MasR axes were noted in DIZE co-treated rats. These findings showed, for the first time, the detailed cardiac deleterious effects of PRG in rats. The underlying pathophysiological mechanism is probably mediated via altered balance between the RAS axes in favor to the ACE/Ang II/AT1R pathway. Accordingly, ACE2 activators might represent promising therapeutic agents for PRG-induced cardiotoxicity.

Graphic Abstract


Pregabalin Diminazene aceturate Cardiotoxicity Angiotensin 1–7 



The authors are thoroughly thankful to Prof. Dr. Maha A. El-Demellawy (City of Scientific Research and Technological Applications, SRTA-City, Alexandria, Egypt) for her efforts in echocardiography. The authors are also grateful to Prof. Dr. Ghada M. Mourad (Center of Excellence for Research in Regenerative Medicine Applications, CERRMA, Faculty of Medicine in Alexandria, Alexandria, Egypt) for her help in histopathological examination.


This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

All applicable international and national guidelines for the care and use of animals were followed. The experiments with animals were approved by the Ethics Committee for Animal Experimentation at Faculty of Pharmacy, Cairo University, Egypt (Permit number: PT 1979).


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pharmacology and Therapeutics, Faculty of Pharmacy and Drug ManufacturingPharos University in AlexandriaAlexandriaEgypt
  2. 2.Department of Pharmacology and Toxicology, Faculty of PharmacyAlexandria UniversityAlexandriaEgypt
  3. 3.Pharmaceutical and Fermentation Industries Development CenterCity of Scientific Research and Technological ApplicationsAlexandriaEgypt
  4. 4.Department of Pharmacology and Toxicology, Faculty of PharmacyCairo UniversityCairoEgypt

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