Effect Of ET_A Receptor Antagonist BQ-123 On Ventricular Remodeling And Cardiac Function After Coronary Microembolization In Rats

Objective:The aim of this study was to establish a model of coronary microembolization (CME) in rats by the use of the autogeneic microthrombotic particles,and to assess whether chronic treatment with BQ-123,an selective ETA antagonist, affect the cardiac function and ventricular remodeling after CME. MethodsWe created a rat model of CME by injecting a suspension of microthrombotic particles into left ventricle when clamping the ascending aorta. The microthrombotic particles were generated from the rat clots. Thirty rats were randomly divided into 3 groups, each consisted of 10 rats: sham-operation group(SO), CME model group(CM), and BQ-123 intervention group(BQ). 3 days after the operation,CME rats were randomized to receive either BQ-123(400ug/kg per day, intraperitoneally) or placebo(normal saline ,0.5ml per day, intraperitoneally ). 1 month after the operation, Echocardiographic Studies and hemodynamic Measurements were conducted.The Transthoracic Doppler echocardiographic studies were performed and left ventricular end-systolic and end-diastolic diameter (LVESD, LVEDD), and left ventricular short-axis fraction shortening(LVFS) and ejection fraction(LVEF) were measured. Cardiac hemodynamics was assessed with a micromanometer-tipped catheter for recording of left ventricular systolic pressure(LVSP),left ventricular end diastolic pressure(LVEDP) and the maximal rate of left ventricular pressure rise(+LVdp/dtmax ). HE staining were conducted to detect micro-myocardial infarction. Sirius-Red staining were conducted to evaluate the content of myocardial collagen. Immunohistochemical analysis show the expression of TNF-α,TGF-β, ETA and ETB receptors in the heart. Plasma endothelin-1(ET-1) and Angiotensin II (AngII) and aldosterone (ALD) and tissue ET-1 were measured by radioimmunoassay.Results1. Echocardiographic StudiesResults from the echocardiographic studies shows that compared with sham-operated group, both LVEDD and LVESD were increased in model group (P<0.01), whereas LVFS and LVEF were significantly decreased;BQ-123 reduced both LVEDD and LVESD but prevented the reduction of LVFS and LVEF.2. Hemodynamic MeasurementsResults from hemodynamic Measurements shows that LVSP and LVEDP and +LVdp/ dtmax markedly reduced in the model group(P<0.01). In contrast, BQ-123 can prevent the reduction of LVEDP and +LVdp/ dtmax.3. Cardiac MorphometryNumbers of focal myocardial infarction increased in model group than the sham group. Compared with the sham rats, collagen volume fraction(CVF) was significantly increased in the CME rats(P<0.01), chronic treatment with BQ-123 reduced the CVF.4. Expression of TNF-αand TGF-βin the heartThe expression of TNF-αand TGF-βin the heart were upregulated significantly in the CME group(P<0.01), BQ-123 can prevent the overexpression..5. Plasma and Tissue ET-1Plasma and tissue ET-1 levels increased in rats in the CM group(P<0.01). ETA receptors and ETB receptors staining in cardiomyocytes was stronger in the CME rats(P<0.01). BQ-123 decreased the ET-1 levels and suspress the overexpression of the endothelin receptors in the rat myocardium.6. Plasma AngII and ALDPlasma AngII and ALD levels increased in rats in the CM group(P<0.01). BQ-123 significantly decreased the plasma levels of AngII and ALD7. Apoptosis index of myocyteCompared to the sham group, Apoptosis index of myocyte in the CME group increased significantly(P<0.01).BQ-123 can prevent the increasion of the apoptosis index.Conclutions1. Ventricular function decreased during the chronic stage of CME with ventricular dilation.2. It was established that neurohomoral systems such as the endothelin system,renin angiotensin system were activated during the chronic stage of CME. Ventricular remodeling progressed due to activation of neurohomoral systems and cytokines, cardiac fibrosis and myocyte apoptosis3. Long term treatment with BQ-123 can prevent ventricular remodeling after CME due to beneficial hemodynamic and cardiac structural effects,as well as supression of the neurohomoral systems and cytokines,and decrese in cardiac fibrosis and myocyte apoptosis.