Dapagliflozin monotherapy and combination therapy with telmisartan ameliorate pregabalin-induced heart failure in rats.

Heart failure (HF) associated with pregabalin (PRG) administration hampers its use in epilepsy, neuropathy and anxiety. Overactivation of cardiac renin angiotensin system (RAS) contributes to PRG-induced HF. The goal of the current study was to investigate the possible cardioprotective effects of dapagliflozin (DAPA), a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, compared with that of the combination therapy of DAPA and telmisartan (Tel) in attenuating PRG-associated HF by examining echocardiographic, morphometric and histopathological parameters. Moreover, to explore the possible beneficial impacts of DAPA and the combination therapy in guarding against PRG-induced myocardial alterations of angiotensin II (Ang II) and angiotensin 1-7 (Ang 1-7) levels, in addition to angiotensin converting enzyme (ACE), angiotensin converting enzyme 2 (ACE2), angiotensin II type 1 (AT1) receptor and Mas receptor (MAS1) levels. Results demonstrated that PRG use lead to echocardiographic, morphometric and histopathological detrimental changes and profoundly elevated ACE, Ang II and AT1 cardiac levels, while reduced cardiac ACE2, Ang 1-7 and MAS1 levels. Concurrent administration of either DAPA monotherapy or the combination therapy counteracted the deleterious echocardiographic, morphometric and histopathological alterations associated with PRG administration and showed notable protection against PRG-associated HF through activation of ACE2/Ang 1-7/MAS1 axis and suppression of ACE/Ang II/AT1 axis. However, the combination therapy group showed more cardioprotective effects than that of DAPA-treated group. The current findings provided the first evidence for the potential protective effects of DAPA monotherapy and combination therapy with Tel against PRG-induced altered balance between the two RAS axes.