福辛普利与厄贝沙坦对大鼠实验性心肌缺血再灌注损伤及心室重构的对比研究
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摘要
在大鼠实验性心肌缺血再灌注损伤模型,福辛普利与厄贝沙坦均可降低心肌缺血再灌注损伤后血清心肌酶的活性,改善左室功能,明显减轻心肌组织水肿以及超微结构的损伤,并抑制氧化应激及心肌细胞凋亡,证实其对心肌缺血再灌注损伤具有保护作用,二者的作用效果相当;心肌缺血再灌注损伤后心肌组织中的caspase-3 mRNA的表达增加,其可能介导了心肌细胞的凋亡;福辛普利与厄贝沙坦均可下调心肌缺血再灌注损伤后的caspase-3 mRNA的表达,可能是其对心肌缺血再灌注损伤产生保护作用的机制之一。
在大鼠实验性心肌梗死所致心室重构模型,福辛普利与厄贝沙坦均能明显改善心室重构后的左心收缩和舒张功能,降低心室壁切应力,有效地防止心肌梗死后左心室扩张和肥厚,二者作用效果无明显差异;福辛普利及厄贝沙坦均可明显降低实验性心肌梗死所致心室重构大鼠血清LPO含量,提高血清SOD、CAT、GSH-Px活性,提示其预防心肌重构作用可能与其提高心肌的抗氧化能力有关;大鼠心肌梗死4周原癌基因c-myc、c-fos、c-jun及fac表达均不明显,福辛普利及厄贝沙坦的抑制作用也未表现出来,提示心室重构后原癌基因的表达已基本结束,在心肌梗死早期抑制原癌基因的高表达,对防治心室重构具有重要意义;大鼠心肌梗死4周后可见凋亡抑制基因Bcl-2的表达减弱,凋亡基因Fas的表达增强,表明心室重构时仍可能伴有心肌细胞凋亡的存在。福辛普利及厄贝沙坦均能促进凋亡抑制基因Bcl-2的表达,并抑制凋亡基因Fas的表达,提示其对抗心肌细胞凋亡的作用可能也是干预心室重构的重要机制之一。
Chepter 1 Effects of Fosinopril and Erbesartan on experimental myocardial ischemia-reperfusion injury in rats
Myocardial reperfusion injury is a paradox by which reperfusion, ultimately needed for long-term tissue survival after prolonged ischemia (myocardial infarction), may potentiate injury to the heart. Characteristics of reperfusion injury after myocardial ischemia involve: myocardial stunning, (reperfusion) arrhythmias, the no-reflow phenomenon (microvascular damage), and/or accelerated cell death. of importance, reperfusion injury may account for as much as 25-60% of the total infarct volume following ischemia and reperfusion. Recently, apoptosis has been implicated in the death of myocardialcytes in animal models of myocardial ischemia and in humans with acute myocardial infarction. Caspases are a conserved family of cysteine proteases that are universal effectors of apoptosis. Although caspases have been shown to mediate cell death in a number of disease processes including ischemia brain injury, their potential role in myocardial infarction is largely unknown. Here we demonstrate that multiple caspases are activated in a rat model of myocardial ischemia and reperfusion, and studied the effect of Fosinopril and Erbesartan on Caspase-3mRNA in cardiac myocytes.
Wistar rats were randomly divided into th four groups: (1) Sham surgical group (n=8); (2) Ischemia-Reperfusion group (n=8) the left anterior descending was occluded for 30 min followed by 24 hours reperfusion; (3) Fosinopril (20mg/kg) group (n=8); (4) Erbesartan (100mg/kg) group (n=8). Fosinopril was fed 24 hours before the coronary artery was occluded and was fed in the morning of the next day. Sham surgical group and Ischemia-Reperfusion group was fed of 0.9% Saline at the same time. Establish myocardial ischemia and reperfusion model as follows:
After anesthetized with ether, rat were faced upward fixed on the operating table. Open the chest between the left third and fourth rib. The heart was exposed. A 0 nylon suture attached to a fine needle was placed under the left anterior descending coronary artery and ligated coronary artery immediately. Return heart into the chest, Squeeze the blood and water out and swiftly close the chest. The time opening the chest is no more than 30 seconds. Sham surgical group placed the suture only but not ligate coronary artery. After 30 min, the ischemia cardialmyocates was reperfused for 24 hours. After that , Left ventricular systolic pressure (LVSP) and peak and end–diastolic LVP and the first derivative of LVP (+dp/dt) were measured by a 2F catheter-tip manometer inserted via the right carotid artery.rats were anesthetized. Blood pressure and heart rate were recorded through femoral arterial cannulatio. Blood was collected through groin aorta. Assay serum AST, LDH, and CK-MB with 7150 automatic biochemical analyzer. The hearts were taken out and perfused with NS through aorta. Crosscut myocardium of left ventricle into four or five slices. Some slices were observed by light microscope and electron microscope. RNA was extracted from myocardial tissue. Use these RNA to RT-PCR, observed the expression of caspase-3 mRNA.
Fosinopril and Erbesartan significant decreased serum CK-MB, LDH, AST activity. This demonstrate that the model of ischemia and reperfusion was good.; Fosinopril and Erbesartan significant improved cardiac function of rats after ischemia and reperfusion. The tissues of myocardium after HE Staining were observed. I/R group: cardiac myocyte plasm was pigmenting deeply, nucleus was concentration, but Fosinopril and Erbesartan group didn’t observed that. Myofilament and myotome of Fosinopril and Erbesartan group were normal on the whole under the electron microscope, but myofilament and myotome of Ischemia-Reperfusion group were broken, intercalated disc structure were not clear. The expression of Caspase-3mRNA of Fosinopril and Erbesartan group were less than that of Ischemia-Reperfusion group.
Fosinopril and Erbesartan may significant decreased serum CK-MB, LDH, AST activity. This illustrate that death of cardiac myocytes is less than I/R group. Fosinopril and Erbesartan can protect cardiac myocytes after ischemia and reperfusion; Fosinopril and Erbesartan may decrease the expression Caspase-3 mRNA. activating Caspase-3 may be the mechanisms of apoptosis.
As above, Fosinopril and Erbesartan can decrease cardiac myocytes of rat in ischemia and reperfusion injury.
Chepter 2 Effects of Fosinopril and Erbesartan on experimental ventricular remodeling in rats
Ventricular remodeling affected badly left ventricular function and prognosis is running through the whole developing process of the patients from acute myocardial infarction, hypertension and congestive heart failure. It is an independent danger fator for the incidence and death rate in cardiovascular diseases.
Acute myocardial infarct model was established as follows:
After anesthetised with ether, rats were face upward fixed on the operating table and the chest was opened between the left third and fourth rib. The heart was exposed. A 0 nylonsuture attached to a fine needle was placed under the left anterior descending coronary artery and ligated coronary artery immediatly. After heart was returned into the chest, blood and water were squeezed out and swiftly close the chest, the time opening the chest is no more than 30 seconds. The suture was placed only to coronary artery but not ligated in rats of sham surgical group. The electrocardiogram was measured so as to corrobrate myocardial infarction after 24 hours of ligating. The rats were randomizied to four groups: group of sham operation (ig normal saline for 4 weeks after sham ligation), AMI group (ig normal saline for 4 weeks after ligation), Fosinopril group (ig Fosinopril 20mg/kg for 4 weeks after ligation) and Erbesartan group (ig Erbesartan 100mg/kg for 4 weeks after ligation). After anaesthesia, ten rats of every group were catheterized for measuring the hemodynamic parameters including HR, SBP, DSP, LVSP, LVEDP and±dp/dtmax. Afterwards, hearts were excised and weighed LVAW and RVAW and measurated LVRW, RVRW, LVV, LVLA and LVSA. The blood samples were from abdomen atery in another ten rats of every group for measuring LPO and NO contents and SOD, CAT, GSH-Px and ACE activities of serum, AngⅡ, NE, E and NO contents and ACE activity of myocardium. In addition, at 4 weeks after ligation, the myocardium of three rats in every group was taken for measuring the expression of proto-oncogene c-fos, c-myc, c-jun, Fac and apoptosis-gene Bcl-2, Bax, p53 and Fas.
At 4 weeks After ligating, the SBP, DBP, MAP, LVSP,±dp/dtmax and±dp/dtmax/LVSP of model group rats were reduced and LVEDP, LVV, LVLA, LVSA, LVAW, LVRW, RVAW and RVRW increased significantly, which indicated that systolic and diastolic function of left ventricle were damaged markedly in rats with ventricular remodeling induced by acute myocardial infarction. At the same time, LPO contents of serum, AngⅡ, E contents and ACE activity of myocardium were increased and NO content and SOD, CAT, GSH-Px activities of serum and NO content of myocardium were decreased markedly, which indicated that RAS of myocardial tissues was concerned with the formation of ventricular remodeling.
The expression of proto-oncogene c-fos, c-myc, c-jun and apoptosis-gene Bax, p53 and Fas of myocardium were increased and the expression of apoptosis-gene Bcl-2 decreasd at 24 hours after ligation, and the expression of apoptosis-gene Bcl-2 was decreasd, Fas increased at 4 weeks after ligation, which indicated that the abnormal expression of proto-oncogene and apoptosis-gene of myocardium were appeard in rats with acute myocardial infarction. The above-mentioned pathological changes can be improved markedly by Fosinopril and Erbesartan.
In conclusion, Fosinopril and Erbesartan can improve systolic and diastolic function of left ventricle, inhibit ventricular dilatation and hypertrophy markedly in rats with ventricular remodeling induced by acute myocardial infarction. The mechanism of Fosinopril and Erbesartan on ventricular remodeling may be involved in the inhibiting the activation of RAS, interdicting promoting growth action of AngⅡand CA, swelling antigrowth action of NO and PGI2, and inhibiting the expression of proto-oncogene c-fos, c-myc, c-jun and apoptosis- gene Bax, p53 and Fas of myocardium and increasing the expression of apoptosis-gene Bcl-2. In addition, the effects of eliminating the free radicals and inhibiting the cell apoptosis in rats with ventricular remodeling induced by acute myocardial infarction were also important.
在大鼠实验性心肌梗死所致心室重构模型,福辛普利与厄贝沙坦均能明显改善心室重构后的左心收缩和舒张功能,降低心室壁切应力,有效地防止心肌梗死后左心室扩张和肥厚,二者作用效果无明显差异;福辛普利及厄贝沙坦均可明显降低实验性心肌梗死所致心室重构大鼠血清LPO含量,提高血清SOD、CAT、GSH-Px活性,提示其预防心肌重构作用可能与其提高心肌的抗氧化能力有关;大鼠心肌梗死4周原癌基因c-myc、c-fos、c-jun及fac表达均不明显,福辛普利及厄贝沙坦的抑制作用也未表现出来,提示心室重构后原癌基因的表达已基本结束,在心肌梗死早期抑制原癌基因的高表达,对防治心室重构具有重要意义;大鼠心肌梗死4周后可见凋亡抑制基因Bcl-2的表达减弱,凋亡基因Fas的表达增强,表明心室重构时仍可能伴有心肌细胞凋亡的存在。福辛普利及厄贝沙坦均能促进凋亡抑制基因Bcl-2的表达,并抑制凋亡基因Fas的表达,提示其对抗心肌细胞凋亡的作用可能也是干预心室重构的重要机制之一。
Chepter 1 Effects of Fosinopril and Erbesartan on experimental myocardial ischemia-reperfusion injury in rats
Myocardial reperfusion injury is a paradox by which reperfusion, ultimately needed for long-term tissue survival after prolonged ischemia (myocardial infarction), may potentiate injury to the heart. Characteristics of reperfusion injury after myocardial ischemia involve: myocardial stunning, (reperfusion) arrhythmias, the no-reflow phenomenon (microvascular damage), and/or accelerated cell death. of importance, reperfusion injury may account for as much as 25-60% of the total infarct volume following ischemia and reperfusion. Recently, apoptosis has been implicated in the death of myocardialcytes in animal models of myocardial ischemia and in humans with acute myocardial infarction. Caspases are a conserved family of cysteine proteases that are universal effectors of apoptosis. Although caspases have been shown to mediate cell death in a number of disease processes including ischemia brain injury, their potential role in myocardial infarction is largely unknown. Here we demonstrate that multiple caspases are activated in a rat model of myocardial ischemia and reperfusion, and studied the effect of Fosinopril and Erbesartan on Caspase-3mRNA in cardiac myocytes.
Wistar rats were randomly divided into th four groups: (1) Sham surgical group (n=8); (2) Ischemia-Reperfusion group (n=8) the left anterior descending was occluded for 30 min followed by 24 hours reperfusion; (3) Fosinopril (20mg/kg) group (n=8); (4) Erbesartan (100mg/kg) group (n=8). Fosinopril was fed 24 hours before the coronary artery was occluded and was fed in the morning of the next day. Sham surgical group and Ischemia-Reperfusion group was fed of 0.9% Saline at the same time. Establish myocardial ischemia and reperfusion model as follows:
After anesthetized with ether, rat were faced upward fixed on the operating table. Open the chest between the left third and fourth rib. The heart was exposed. A 0 nylon suture attached to a fine needle was placed under the left anterior descending coronary artery and ligated coronary artery immediately. Return heart into the chest, Squeeze the blood and water out and swiftly close the chest. The time opening the chest is no more than 30 seconds. Sham surgical group placed the suture only but not ligate coronary artery. After 30 min, the ischemia cardialmyocates was reperfused for 24 hours. After that , Left ventricular systolic pressure (LVSP) and peak and end–diastolic LVP and the first derivative of LVP (+dp/dt) were measured by a 2F catheter-tip manometer inserted via the right carotid artery.rats were anesthetized. Blood pressure and heart rate were recorded through femoral arterial cannulatio. Blood was collected through groin aorta. Assay serum AST, LDH, and CK-MB with 7150 automatic biochemical analyzer. The hearts were taken out and perfused with NS through aorta. Crosscut myocardium of left ventricle into four or five slices. Some slices were observed by light microscope and electron microscope. RNA was extracted from myocardial tissue. Use these RNA to RT-PCR, observed the expression of caspase-3 mRNA.
Fosinopril and Erbesartan significant decreased serum CK-MB, LDH, AST activity. This demonstrate that the model of ischemia and reperfusion was good.; Fosinopril and Erbesartan significant improved cardiac function of rats after ischemia and reperfusion. The tissues of myocardium after HE Staining were observed. I/R group: cardiac myocyte plasm was pigmenting deeply, nucleus was concentration, but Fosinopril and Erbesartan group didn’t observed that. Myofilament and myotome of Fosinopril and Erbesartan group were normal on the whole under the electron microscope, but myofilament and myotome of Ischemia-Reperfusion group were broken, intercalated disc structure were not clear. The expression of Caspase-3mRNA of Fosinopril and Erbesartan group were less than that of Ischemia-Reperfusion group.
Fosinopril and Erbesartan may significant decreased serum CK-MB, LDH, AST activity. This illustrate that death of cardiac myocytes is less than I/R group. Fosinopril and Erbesartan can protect cardiac myocytes after ischemia and reperfusion; Fosinopril and Erbesartan may decrease the expression Caspase-3 mRNA. activating Caspase-3 may be the mechanisms of apoptosis.
As above, Fosinopril and Erbesartan can decrease cardiac myocytes of rat in ischemia and reperfusion injury.
Chepter 2 Effects of Fosinopril and Erbesartan on experimental ventricular remodeling in rats
Ventricular remodeling affected badly left ventricular function and prognosis is running through the whole developing process of the patients from acute myocardial infarction, hypertension and congestive heart failure. It is an independent danger fator for the incidence and death rate in cardiovascular diseases.
Acute myocardial infarct model was established as follows:
After anesthetised with ether, rats were face upward fixed on the operating table and the chest was opened between the left third and fourth rib. The heart was exposed. A 0 nylonsuture attached to a fine needle was placed under the left anterior descending coronary artery and ligated coronary artery immediatly. After heart was returned into the chest, blood and water were squeezed out and swiftly close the chest, the time opening the chest is no more than 30 seconds. The suture was placed only to coronary artery but not ligated in rats of sham surgical group. The electrocardiogram was measured so as to corrobrate myocardial infarction after 24 hours of ligating. The rats were randomizied to four groups: group of sham operation (ig normal saline for 4 weeks after sham ligation), AMI group (ig normal saline for 4 weeks after ligation), Fosinopril group (ig Fosinopril 20mg/kg for 4 weeks after ligation) and Erbesartan group (ig Erbesartan 100mg/kg for 4 weeks after ligation). After anaesthesia, ten rats of every group were catheterized for measuring the hemodynamic parameters including HR, SBP, DSP, LVSP, LVEDP and±dp/dtmax. Afterwards, hearts were excised and weighed LVAW and RVAW and measurated LVRW, RVRW, LVV, LVLA and LVSA. The blood samples were from abdomen atery in another ten rats of every group for measuring LPO and NO contents and SOD, CAT, GSH-Px and ACE activities of serum, AngⅡ, NE, E and NO contents and ACE activity of myocardium. In addition, at 4 weeks after ligation, the myocardium of three rats in every group was taken for measuring the expression of proto-oncogene c-fos, c-myc, c-jun, Fac and apoptosis-gene Bcl-2, Bax, p53 and Fas.
At 4 weeks After ligating, the SBP, DBP, MAP, LVSP,±dp/dtmax and±dp/dtmax/LVSP of model group rats were reduced and LVEDP, LVV, LVLA, LVSA, LVAW, LVRW, RVAW and RVRW increased significantly, which indicated that systolic and diastolic function of left ventricle were damaged markedly in rats with ventricular remodeling induced by acute myocardial infarction. At the same time, LPO contents of serum, AngⅡ, E contents and ACE activity of myocardium were increased and NO content and SOD, CAT, GSH-Px activities of serum and NO content of myocardium were decreased markedly, which indicated that RAS of myocardial tissues was concerned with the formation of ventricular remodeling.
The expression of proto-oncogene c-fos, c-myc, c-jun and apoptosis-gene Bax, p53 and Fas of myocardium were increased and the expression of apoptosis-gene Bcl-2 decreasd at 24 hours after ligation, and the expression of apoptosis-gene Bcl-2 was decreasd, Fas increased at 4 weeks after ligation, which indicated that the abnormal expression of proto-oncogene and apoptosis-gene of myocardium were appeard in rats with acute myocardial infarction. The above-mentioned pathological changes can be improved markedly by Fosinopril and Erbesartan.
In conclusion, Fosinopril and Erbesartan can improve systolic and diastolic function of left ventricle, inhibit ventricular dilatation and hypertrophy markedly in rats with ventricular remodeling induced by acute myocardial infarction. The mechanism of Fosinopril and Erbesartan on ventricular remodeling may be involved in the inhibiting the activation of RAS, interdicting promoting growth action of AngⅡand CA, swelling antigrowth action of NO and PGI2, and inhibiting the expression of proto-oncogene c-fos, c-myc, c-jun and apoptosis- gene Bax, p53 and Fas of myocardium and increasing the expression of apoptosis-gene Bcl-2. In addition, the effects of eliminating the free radicals and inhibiting the cell apoptosis in rats with ventricular remodeling induced by acute myocardial infarction were also important.
引文
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