Pharmacological Study Of The Therapeutic Outcomes Of Rosuvastatin And Beta-Blocker Combination In Isoprenaline- Induced Myocardial Infarction In Rats

Abstract

Myocardial infarction (MI) is a major form of ischemic heart disease characterized by an inequity of coronary blood supply and demand, leading to cardiac ischemia and cardio¬myocytes degeneration. Rosuvastatin has been shown to activate PI3K/Akt/Nrf2/HO-1 pathway, which plays a pivotal role in promoting cell survival in the myocardium. Method: The present study investigated the therapeutic benefit of adding rosuvastatin (RSV 20 mg/kg; orally) to low-dose carvedilol (CAR 2 mg/kg; orally) in protection against myocardial infarction (MI) induced by Isoprenaline (ISP) in rats. Results: The results showed that low-dose CAR and/or RSV pre-treatment prevented ECG changes and histopathological alterations induced by ISP. Also, the same treatments significantly reduced the infarct size, heart index, serum creatine kinase-MB (CK-MB), cardiac troponin-I (cTn-I), and C-reactive protein (CRP) levels. In addition, pre- treatment with low-dose CAR and/or RSV replenished the antioxidant defense systems, superoxide dismutase (SOD) and total antioxidant capacity (TAC) with subsequent reduction in heart tissue lipid peroxides. Further, pre-treatment with RSV and/or CAR showed lower expression level of the inflammatory transcription factor NF-κB (p65) and a significant increase in phosphorylated PI3K and Akt, which may in turn activate the anti-apoptotic signaling events as evidenced by the decrease in active caspase-3 level. The combination therapy has more significant and potent effect in the most studied parameters as compared to their monotherapy. The protective effect of the proposed combination may be, at least partly, via activation of Nrf2/HO-1 signaling and the involvement of the PI3K/Akt pro-survival signaling pathway. Conclusion: This study highlights the potential benefits of combining RSV with low-dose CAR in affording myocardial protection against ISP-induced MI in rats; via attenuating oxidative stress, inflammation and apoptosis. Furthermore, the activation of Nrf2, by RSV in combination with low-dose CAR, suggests that targeting Nrf2 activation may represent a novel therapeutic approach in the treatment of myocardial infarction.These findings provide experimental evidence for extending the use of this combination to the clinical practice