Novel HM12, A Selective Inhibitor of L‐/T‐type Calcium Channels, Averts Doxorubicin Cardiotoxicity in Male Wistar Rats

Abstract

Doxorubicin is a cytotoxic anthracycline anticancer drug that is limited by its cardiotoxic action. This study sought to investigate the cardiopreventive potential of HM12, a 1,4‐dihydropyridine (DHP) derivative (CCB) against doxorubicin induced cardiotoxicity in male Wistar rats. HM12 was synthesized as a DHP‐based hexahydroquinoline derivative (2‐[(2‐methylacryloyl)oxy]ethyl 4‐(3,5‐dibromo‐2‐hydro[1]xyphenyl)‐2,6,6‐trimethyl‐5‐oxo‐1,4,5,6,7,8‐hexahydroquinoline‐3‐carboxylate) according to the modified Hantzsch reaction via condensation reactions under microwave irradiation. HM12 structure was confirmed using infrared, proton, and carbon‐13 nuclear magnetic resonance, and mass spectra. The CCB activity was evaluated using whole‐cell patch‐clamp assays. Further, fourty‐eight adult male Wistar rats were divided into eight groups of 6/group and received distilled water saline; doxorubicin (DOX, 20 mg/kg, i.p.), HM12 lower (HM12LD) or upper (HM12UD) dose (5 or 20 mg/kg, p.o.), nifedipine (NFD, 20 mg/kg), and their combinations. All rats were sacrificed 24 h after the last administration and changes in blood pressure (BP), heart rate (HR), biochemical, oxidative stress indices, and heart histology were assessed. DOX cardiotoxicity produced spontaneous increased (p<0.05) BP (baseline 106.5/84 mmHg (day 1) versus 170/173.5 mm/Hg (59.6/72%, day 6) and 173.5/167 mmHg (98.8/69.1%, day 7) with altered HR (baseline 99 beats per minutes versus 167.5 bpm (69.1%, day 7). Also, DOX‐treated rats showed a significant increase in tumor necrosis factor‐α (TNF‐α), c‐reactive protein (CRP), and lactate dehydrogenase (LDH). This was accompanied by an increase (p<0.05) in cardiac malondialdehyde (MDAc) and decreased reduced glutathione (GSHc) levels, and activities of catalase (CATc) and superoxide dismutase (SODc). However, HM12UD + DOX had changes BP (baseline 106.5/96 mmHg (day 1) versus 181/179.5 mmHg (70.1/87%, day 6) versus 135/127 mmHg (26.8/32.3%, day 7) with HR (baseline 93.5 beats per minutes versus 164.5 bpm (75.9%, day 6) to 127 bpm (35.8%, day 7). Also, HM12UD was effective against IL‐6, CRP, LDH but not TNF‐α. Further, HM12UD significantly reversed DOX‐induced MDAc by elevating antioxidants GSHc levels as well as activities of CATc and SODs in the treated animals. Additionally, HM12UD averted histopathological changes observed in the rat heart due to DOX intoxication. Overall, the present study conferred new evidence on the protective effects CCBs, in particular, HM12 on DOX‐induced cardiotoxicity, oxidative stress, tumor biomarkers, and cardiac histological changes in rats.