Differential Effects of Ivabradine and Metoprolol on Cardiovascular Remodeling and Myocardial Infarction Induced by Isoprenaline in Chronic N-nitro-L-arginine Methyl Ester (L-NAME) Treated Rats

Background: Elevated heart rate is associated with cardiovascular morbidity and mortality in the general population and in patients with cardiovascular disease Aim: This study was designed to investigate the effects of the two bradycardiac agents ivabradine and metoprolol on cardiovascular changes and the infarction size induced by isoprenaline in chronic N-nitro-L-arginine methyl ester (L-NAME) treated rats. Methods: Four groups of male Wistar rats were studied: the 1st group served as a normal control, the 2nd received L-NAME (100 mg/kg), the 3rd group was treated with the same dose of L-NAME plus ivabradine (10 mg/kg) and the 4th group was treated with the same dose of L-NAME plus metoprolol (150 mg/kg). All treatments were administered daily by gastric gavage. After 6 weeks of L-NAME and drug treatment myocardial infarction was induced by isoprenaline injection (11 mg/100g/day for 2 consecutive days). The following parameters were assessed; systolic blood pressure, electrocardiographic changes, cardiac enzymes, and histopathological examination of heart tissues, aorta & coronary vessels. Moreover, vascular reactivity of the isolated aortic rings to phenylephrine and acetylcholine was tested. Results: Ivabradine and metoprolol administration to L-NAME/isoprenaline treated rats significantly reduced heart rate, microvascular remodeling, infarct size, serum lactate dehydrogenase, serum creatine kinase and attenuated the mortality resulting from isoprenaline-induced infarction. Pretreatment with ivabradine had non-significant effect on L-NAME-induced hypertension and cardiac hypertrophy, in contrast to metoprolol pretreatment. Selective heart rate reduction with ivabradine improved endothelial dysfunction, and reduced atherosclerotic plaque formation in L-NAME treated rats. On the contrary, metoprolol showed insignificant improvement of endothelial dysfunction as evidenced by assessment of mean EC50 and Emax of phenylephrine-induced contraction and by considering the mean percent of acetylcholine-induced relaxation in comparison to the L-NAME/isoprenaline treated group. Conclusion, these results suggest that ivabradine has a significant protective effect against isoprenaline-induced myocardial infarction with improvement of endothelial dysfunction in chronic L-NAME-treated rats