Thesis (Ph.D.) - Cairo University - Faculty of Pharmacy - Department of Pharmacology and Toxicology

Pregabalin (PRG) is highly effective in the treatment of epilepsy, neuropathic pain and anxiety disorders. Despite its potential benefits, PRG administration has been reported to induce or exacerbate heart failure (HF). Overactivation of renin angiotensin system (RAS) plays a pivotal role in HF pathophysiological mechanism. To further emphasize the role of RAS in PRG-induced HF pathological mechanism, the protective potential of diminazene aceturate (DIZE), an angiotensin converting enzyme 2 (ACE2) activator, was investigated. PRG administration induced morphometric, echocardiographic and histopathological deleterious alterations and significantly elevated cardiac angiotensin II (Ang II), angiotensin converting enzyme (ACE) and angiotensin II type 1 receptor (AT1R) levels, while reduced angiotensin 1-7 (Ang 1-7), ACE2 and Mas receptor (MasR) cardiac levels. DIZE co-administration showed prominent protection against PRG-induced cardiac alterations in rats. 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. Moreover, the current study examined the possible cardioprotective effect of telmisartan (Tel), an AT1R blocker, compared with that of captopril (Cap), an ACE inhibitor, in ameliorating PRG-induced HF in rats by assessing morphometric, echocardiographic and histopathological aspects. Furthermore, the role of RAS modulation by the two drugs in guarding against PRG-induced changes in cardiac Ang 1-7 and Ang II levels, in addition to myocardial expression of ACE2, ACE, MasR and AT1R was investigated

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