Effect Of Allopurinol On Left Ventricular Remodeling And Function In Rats With Myocardial Infarction

Backgroud and Objective: Ventricular remodeling after myocardial infarction(MI) includes the remodeling of cardiomyocyte and interstitial substance, that is, the expansion of the infarction area, myocardial hypertrophy in non-infarcted zones(NIZ) and cavity dilation, which ultimately lead to LV dysfunction. Myocardial interstitial remodeling was reflected by the dynamic changes of categories, quantities, proportions and distribution of the interstitial collagen, among which typeⅠandⅢcollagens have a great role in maintaining the integrity of the myocardial tissue. So the relative changes of the two can reflect the myocardial interstitial remodeling. A comprehensive evaluation of the collagen deposition and the dynamic changes of the ratio of typeⅠandⅢcan reflect the process of the collagen remodeling after MI. Cardiomyocyte apoptosis also plays a major role in left ventricular remodeling and dysfunction after MI. A large amount of reactive oxygen species produced in the ischemic myocardium can induce cardiomyocyte apoptosis. Accumulating evidence suggests that in the ischemic myocardium there were both an increased expression and activity of xanthine oxidase which mediates myocardial hypertrophy and cavity dilatation by means of producing a lot of reactive oxygen species. Therefore, this study sought to investigate the effect of xanthine oxidase inhibitor allopurinol on left ventricular remodeling and function, the remodeling of cardiomyocyte and interstitial substance in rats with myocardial infarction.Methods:Myocardial infarction models were produced by ligation of anterior descending coronary artery. The survivals were randomly divided into 3 groups: sham operation group, MI group and allopurinol group (50 mg/kg·day). On the 7th , 14th , 21st and 28th day respectively, the collagen content were mesured by colorimetry. The typeⅠand typeⅢcollagen volume fraction (CVF) andⅠ/Ⅲratio in infarcted and non-infarcted zones (NIZ) were examined with Picrosirius red staining (PRS) and the mRNA expressions in NIZ were detected with RT-PCR. The activities of xanthine oxidase and .O2-, .OH-scavenging in NIZ were mesured by colorimetry. On the 28th day, the parameters of echocardiogram and hemodynamics were investigated. The infarct size, LV mass index were detected, too. In NIZ, the apoptosis index (AI) was detected by TUNEL and the expression of Fas was detected by immunohistochemistry, as well as the expression of xanthine oxidase and Caspase 3 were detected by Western blot.Results:Compared with sham group, The myocardial collagen content in MI group had increased sharply on the 7th day and then began to decrease after it reached the peak on the 14th day after the operation(P <0.01). The typeⅠCVF in MI group had increased sharply on the 7th day and later decreased a litter after it reached the peak on the 14th day; the typeⅢCVF had also increased sharply on the 7th day and later began to decrease very slowly(P <0.01); the ratio ofⅠ/Ⅲwas much lower than that in sham group on the 7th day, and then it began to rise and reached the peak on the 14th day, and later fell to the level of sham group on the 28th day (P <0.01).The typeⅠcollagen mRNA in MI group had increased sharply on the 7th day and went on increasing on the 14th day, and then it had decreased to a certain degree on the 21st day but still remained high; the typeⅢcollagen mRNA had also increased and reached the peak on the 7th day and then tended to decrease, but still remain significantly higher than that in sham group on the 21st day(P <0.01).The activities of .O2- and .OH-scavenging of the myocardial tissue in MI group had both decreased sharply, but the xanthine oxidase activity had increased significantly at different time points (P <0.01).On the 28th day, the 1eft ventricular(LV) mass and LV mass index in MI group had increased significantly; the interventricular septum(IVS) and left ventricular posterior wall (LVPW) got thicker; the left ventricular end-diastole diameter(LVEDD) and left ventricular end-systole diameter(LVESD) got wider; the left ventricular end-diastolic pressure(LVEDP) increased while left ventricular systolic pressure(LVSP) decreased; the ejection fraction(EF) and fractional shortening(FS) decreased(P <0.01).The AI and expression of Fas, xanthine oxidase, Caspase 3 in NIZ had significantly increased in MI group (P <0.05 or P <0.01).Compared with MI group, the changes of these parameters above were alleviated in allopurinol group (P <0.05 or P <0.01). However, there were no significant difference in typeⅠand typeⅢCVF in infarcted zone and heart rate, arterial blood pressure, infarct size, xanthine oxidase expression between allopurinol and MI group(P >0.05).Conclusion: Allopurinol could markedly inhibit the the remodeling of cardiomyocyte and interstitial substance and improve left ventricular function. The mechanism could be related to its ability to depress the activity of xanthine oxidase, reduce reactive oxygen species, inhibit the cardiomyocyte apoptosis in rats with MI.