Animal Study To Compare Ivabradine With Atenolol On Effectiveness In Preserving Coronary Reserve And Preventing Ventricular Remodeling After Myocardial Infarction

Part Ⅰ Comparative Study of the Effects Preserving on Coronary Reserve between Ivabradine and Atenolol in Rats with Myocardial InfarctionObjective To compare Ivabradine therapy with Atenolol therapy on the effects of preserving coronary reserve in rats with myocardial infarction.Methods In this study,12-month-old male Sprague-Dawley rats were divided into four groups:SHAM group, MI group, MI+IVA group and MI+Atenolol group.There were 8 to 12 rats involved in each group. Some of them were induced to acute myocardial infarction by complete ligation of the left coronary artery. Medical Treatment with Ivabradine or Atenolol started after myocardial infarction immediately and continued until the 28th day. EKG was recorded on both the first day and the 28th day to measure the heart rate of those rats in MI+IVA group and MI+Atenolol group. UCG examination was carried out on the 28th day to determine the area of infarted myocardium. Moreover, mean artery pressures and coronary blood flows were measured before and after the coronary dilation to evaluate the coronary reserve on the 30th day. We use nonparametric tests to search the differences between or among the different groups.Results There were no significant statistic differences in basic heart rate as well as the reduction of heart rate after the medical therapy between MI-IVA group and MI-AT group. Also, there were no statistic differences in the infarct areas amony MI group、MI-IVA group and MI-ATgroup. Among the four groups, the basic coronary blood flows and coronary conductance of the MI+IVA group were the lowest, while after coronary dilation the MI group’s coronary blood flows and coronary conductance were the lowest. But there was no statistic difference in the mean artery pressures, the coronary blood flows and coronary conductance before or after the dilation among the 4 groups. Comparing with SHAM group, the coronary reserve of both the free wall and the ventricular septum in MI group was significantly lower, and the coronary reserve of the ventricular septum in MI+Atenolol group was also significantly lower. The coronary reserve of both the free wall and the ventricular septum in MI+IVA group was higher than those of MI group and MI+Atenolol group.Conclusion The coronary reserve of rats with myocardial infarction could be well protected after 28 days of ivabradine treatment, while this effect couldn’t appear after the atenolol treatment. Because the mechanisms inducing the heart rate reduction are different between ivabradine and atenolol, their effects on the neuroendocrine system, molecular metabolism of the body may also be different. These may be the reasons to explain the different protecting effects of the two drugs on the coronary reserve.Part II Comparison of the Effects on Infarction Size and Heart Function in Rats with Myocardial Infarction between Ivabradine and Atenolol TreatmentObjective To compare ivabradine therapy with atenolol therapy on the effects of infarction area and heart function in rats with myocardial infarction.Methods In this study, rats were divided into two groups:MI-IVA group and MI-AT group. All rats were induced to myocardial infarction by complete ligation of the left coronary artery. Medical Treatment started after myocardial infarction immediately. On the 7th day and the 14th day after myocardial infarction eight rats from each group were sacrificed to get the left ventricle. Masson’s staining was employed to distinguish the infarction and no-infarction region. The infarction area was calculated by morphometric analysis. The echocardiographs of the rest rats were recorded on the 2nd day and the 30th day.Results There was no difference in infarction area between MI-IVA group and MI-AT group on 7th day. After two weeks the infarction area of MI-IVA group was significantly smaller than that of MI-AT group though there was no difference among those echocardiographic parameters taken 24h after the infarction or on the 30th day.Conclusion Ivabradine treatment for a relatively long period after mycardial infarction could reduce the sign of infarction.Part III Comparing Ivabradine with Atenolol on the Effect of Vascular Growth Factor Receptors in Infarcted MyocardiumObjective To compare ivabradine therapy with atenolol therapy on the effect of vascular growth factor receptors in infarcted myocardium.Methods In this study, rats were divided into three groups:MI group, MI-IVA group and MI-AT group. All rats were induced to myocardial infarction by complete ligation of the left coronary artery. Medical Treatment started after myocardial infarction immediately and continued until the 7th day or the 14th day. Then the rats were sacrificed to get the myocardial tissue of both the left ventricular free wall and the septum. The myocardial concentrations of both Flk-1 and Tie-2 were determined by western blot. We used independent t test to search the differences between or among the groups.Results One week later, the concentration of Flk-1 in the septum of rats treated with atenolol was significantly lower than that in rats treated with ivabradine, and the concentration of Tie-2 in the left ventricular free wall of rats treated with atenolol was also significantly lower than that in rats treated with ivabradine. After two weeks, the concentration of Tie-2 in the left ventricular free wall of rats treated with ivabradine was significantly higher than that in rats treated with atenolol.Conclusion The concentrations of the two kinds of vascular growth factor receptors in infarcted rats treated with ivabradine were generally higher, comparing to the concentrations of rats treated with atenolol. Thus, ivabradine treatment may induce more vascular growth and preservation of coronary reserve than atenolol treatment.Part IV Comparing Ivabradine Therapy with Atenolol Therapy on the Effects of the Density of Arteriole in Myocardium of Infarcted RatsObjective To compare the effect on the density of arteriole in infarcted myocardium between ivabradine therapy and atenolol therapy.Methods In this study, rats were divided into two groups:MI-IVA group and MI-AT group. All rats were induced to myocardial infarction by complete ligation of the left coronary artery. Medical Treatment started after myocardial infarction immediately and continued until the 28th day, Then the rats were sacrificed to get the myocardial tissue of both the left ventricular free wall and the septum on the 30th day. The density of arteriole in infarcted myocardia was determined by immune-tissue chemistry and morphometric analysis. We used independent t test to search the differences between the two groups.Results There was no difference between the two groups, in the density of arteriole of either left ventricular free wall or septum.Conclusion Ivabradine treatment has stimulated the growth of arteriole to the same extent of what atenolol treatment does.Part Ⅴ Comparitive Study of Ivabradine Therapy with Atenolol Therapy on the Effects of Collagen in Myocardium and Perivascular Collagen of Infarcted RatsObjective To compare the effects on the collagen in myocardium and around myocardial vessels in rats with myocardial infarction between ivabradine therapy and atenolol therapy.Methods In this study, rats were divided into two groups:MI-IVA group and MI-AT group. All rats were induced to myocardial infarction by complete ligation of the left coronary artery. Medical treatment started after myocardial infarction immediately and continued until the 28th day. On the 28th day after myocardial infarction, the rats were sacrificed to get the myocardial tissue of the left ventricular free wall. Picrosirius red staining was employed to display the collagen fibers in myocardium around myocardial vessels.Results The picrosirius red staining images were shown at equal level within each group, but there was significant difference between the two groups. Both interstitial collagen and perivascular collagen of post-MI rats in MI-IVA group were less than that of MI-AT group.Conclusion The preservation of coronary reserve by ivabradine is at least partly related to the reduction of collagen in the interstitial myocardium or surrounding the myocardial vessels.