Thesis (M.Sc.) - Cairo University - Faculty of Pharmacy - Department of Pharmacology and Toxicology

Methods: ISO was injected subcutaneously for 2 consecutive days at doses of 85 and 170 mg/kg/day, respectively. Nicorandil (3 mg/kg/day) was then given orally with or without a single intravenous injection of BM-MSCs. Electrocardiography and echocardiography were recorded 2 weeks after the beginning of treatment. Rats were then sacrificed and ventricles were isolated for estimation of tumor necrosis factor-alpha, vascular endothelial growth factor and transforming growth factor-beta. Moreover, protein expressions of caspase- 3, connexin- 43 as well as inducible and endothelial nitric oxide synthases were evaluated. Finally, histological studies of myocardial fibrosis and blood vessel density were performed and cryosections were done for estimation cell homing. Results: ISO-induced HF was characterized by significant increase in heart weight index in addition to significant decrease in cardiac conduction and ejection fraction as demonstrated by electrocardiographic and echocardiographic changes. Moreover, myocardial inflammation, fibrosis, apoptosis and angiogenesis were significantly observed. Additionally, myocardial conduction was significantly impaired as estimated by connexin-43 protein expression. Combined nicorandil/BM-MSCs therapy provided an additional improvement compared to cell therapy alone towards reducing ISO-induced cardiac hypertrophy, fibrosis and inflammation. Notably, combined therapy induced significant increase in angiogenesis and cell homing and prevented ISO-induced changes in contractility and apoptotic markers. Conclusion: Combined nicorandil/BM-MSCs therapy was superior to cell therapy alone towards preventing ISO-induced HF in rats through creation of a supportive environment for mesenchymal stem cells

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