Therapeutic Effects Of Continuous Infusion Brain Natriuretic Peptide On Post Myocardial Infarction Ventricular Remodeling In Rats

The natriuretic peptides (NPs) atrial natriuretic peptide (ANP) and brain natriuretic peptide(BNP) play important roles in maintaining cardiorenal homeostasis under physiological and pathological conditions. The release of the stored peptides is especially associated with conditions of alterd chamber loading and myocyte stretch. BNP release and induction has been documented in experimental acute myocardial infarction, BNP concentration in the infarcted and noninfarcted region of left ventricle increased about 5-fold 24 hours postinfarction. Recent studies shown, BNP limit the extent of tissue infarction during ischaemia and reperfusion, the mechanism of its cytoprotection action is related to cGMP accumulation, opening of ATP-sensitive K+ channels and nitric oxide synthase. The longer-term upregulation of BNP expression in the heart postinfarction could suppress the growth and proliferation response in myocytes and fibroblasts, whereas BNP knockout mice exhibit marked cardiac fibrosis. The chronic elevation of BNP level in the myocardium postinfarction maybe inhibits the pro-hypertrophic and pro-fibrotic action mediated by angiotensinâ…¡ and catecholamine. In basic and clinical study, BNP has been shown to decrease collagen especially typeâ… collagen synthesis which are close related to ventricular remodeling. Thus, BNP is probably beneficial to prevent postinfarction ventricular remodeling and heart function protection. The elevation of intrinsic BNP is insufficient, so extrinsic BNP infusion may be effective on cytoprotection and infarct size limitation in acute phase of myocardial infarction, and continuous BNP infusion probably has long-term effect such as inhibiting ventricle remodeling and preventing heart failure. In the setting of MI, Hillock et al have showed that short-term delivery of nesiritide for 60 hours in patients soon after MI can improve ventricular remodeling associated with increments in plasma cGMP. However, the result of vitro study shows high dose BNP could increase MMPs(MMP-1,-2,-3) expression which are harmful to ventricle remodeling. Transgenic mice model of BNP overexpression exhibits elevation of MMP expression and sudden cardiac death due to cardiac rupture, which constitutes a potential barrier for its clinical application to treat patients against cardiac remodeling post myocardial infarction.Acute myocardial infarction companied with hyperglycemia is common in the clinic. In cardiomyocyte/endothelial cell cultures, ACEI efficacy is abolished by high-glucose-induced endothelial NO dysfunction. There is evidence that antihypertrophic ACEI efficacy is compromised in diabetes patients. The antihypertrophic actions of BNP, which stimulate cGMP independently of NO, are preserved in cardiomyocytes despites high-glucose-induced endothelial dysfunction. Further study is needed to estimate the protective efficacy of ACEI and BNP post myocardial infarction companied with hyperglycemia.Our present study was designed for the following purposes: 1), to test if continous infusion of exogenous BNP would still exert the protective effect against remodeling after MI without the risk of cardiac rupture; 2), how the expression level of MMPs as well as its inhibitor TIMP-1 was affected by chronic BNP infusion; 3), to compare protective effects between chronic BNP infusion and enalapril administration and 4) to compare post-infarction protective effects between chronic BNP infusion and enalapril administration in diabetes rats.Type 1 diabetes model is established by streptozocin. Diabetes and non-diabetes Rats with coronary ligation were randomly assigned to the following 4 groups respectively: 1) sham-operated control rats; 2) MI group rats; 3) MI rats given enalapril treatment and 4) MI rats with continuous BNP infusion. Rats were closely monitored and then sacrificed on 3days(only non-diabetes Rats), 7days and 28days after operation.Exogenous BNP infusion can maintain comparatively a higher BNP level in heart tissue .Compared with the MI group rats, both enalapril and BNP treatment resulted in similar protective effects against ventricular remodeling, as evidenced by improved cardiac performance and hemodynamic parameters. These beneficial effects were associated with increased cardiac tissue cGMP concentration and attenuated collagen deposition in non-infarcted area.MMP expressions were differently suppressed by enalapril, but not by BNP infusion. However, higher TIMP expression was induced only by BNP therapy, No cardiac rupture was detected at autopsy in rats with BNP infusion.There was no difference between enalapril and BNP therapy on post-infarction heart function protective in diabetes rats. But BNP was more effective on collagen deposition inhibition than enalapril in diabetes rats with higher cGMP concentration.In conclusion, continuous BNP infusion could attenuate cardiac hypertrophy, LV enlargement and collagen deposition, improve heart function after myocardial infarction without influence on MMPs expression. It plays an important role on cardiac protection post infarction. Hyperglycemia attenuates the anti-collagen deposition action of enalapril but has no influence on that of BNP maybe for their different protective mechanism.