Effects of benazepril on cardiac function,free oxygen radicals,sarcoplasmic reticulum Ca2+-ATPase following cardiac ischemia-reperfusion in spontaneously hypertensive rats

AIM: To investigate the effects of angiotensin converting enzyme inhibitor (ACEI), benazepril (B), on cardiac function , free oxygen radicals, sarcoplasmic reticulum(SR) Ca²⁺-ATPase following ischemia-reperfusion in sportaneously hypertensive rats (SHRs). METHODS: Thirty 10-week-old female SHRs were randomly assigned into two groups: group SHR was control; The animal in group SHR+B was given with 10 mg/kg of benazepril per day. Another 15 Wistar rats with the same age and sex were normal control (group Wistar). After 12 weeks of pretreatment, all rats in each group were subjected to 30 min of left anterior descending coronary artery occlusion and 30 min of reperfusion. Hemodynamic parameters, left heart-to-body weight ratio (LVW/BW), myocardial malondialdehyde (MDA) concentration, superoxide dismutase (SOD) activity, and SR Ca²⁺-ATPase activity were measured. RESULTS: Compared to group Wistar, the rats in group SHR had higher blood pressure, LVW/BW and myocardial MDA concentration, more serious left cardiac function injury and lower myocardial SOD activity and SR Ca²⁺-ATPase activity; group SHR+B had lower myocardial MDA concentration, higher myocardial SOD activity, but no difference in blood pressure, LVW/BW, the degree of left cardiac function injury and myocardial SR Ca²⁺-ATPase activity. CONCLUSION: Benazepril can attenuate ischemia-reperfusion-induced cardiac function injury by regression of left ventricular hypertrophy (LVH), improving SR Ca²⁺-ATPase activity and decreasing oxygen free radicals injury in SHRs.     

Relationship of microRNA-133a and TGF-β1 protein in myocardial tissues of spontaneously hypertensive rats

AIM：To observe the changes of microRNA-133a and transforming growth factor β1 (TGF-β1) protein in the myocardium of spontaneously hypertensive rats (SHR). METHODS：Male SHR (18 weeks old, n=12) and male Wistar-Kyoto rats (WKY, 18 weeks old, n=12) served as SHR group and control group, respectively. Caudal arterial blood pressure was detected by a noninvasive blood pressure measurement and analysis system. Myocardial collagen volume fraction (CVF) and perivascular collagen area ratio (PVCA) were determined by Masson staining. The level of miR-133a in the heart was detected by real-time quantitative PCR. The protein level of TGF-β1 in the heart was also analyzed by the methods of immunohistochemisty and Western blotting. RESULTS：Compared with control group, systolic and diastolic blood pressure, CVF and PVCA significantly increased, the expression of TGF-β1 protein was significantly up-regulated, and the level of miR-133a was significantly reduced in SHR group. In SHR group, the expression of miR-133a was decreased to (23.9±4.6)% in control group. A negative correlation between the levels of miR-133a and TGF-β1 protein in SHR group was observed (r=-0.791, P<0.01). CONCLUSION：The level of miR-133a is down-regulated along with the up-regulation of TGF-β1 protein expression and collagen synthesis in the myocardial tissues of SHR. miR-133a and TGF-β1 may be involved in myocardial fibrosis in SHR.     

Inhibitory effect of aerobic exercise on left ventricular remodeling and sympathetic neural remodeling in rats with heart failure after myocardial infarction

AIM: To investigate the effects of long-term aerobic exercise on the heart and sympathetic neural remodeling (structure and function remodeling) in heart failure rats induced by myocardial infarction. METHODS: Heart failure model after myocardial infarction was performed by ligating anterior descending coronary artery in the Wistar rats. Four weeks after operation, the rats were randomly divided into sham operation sedentary (S) group, heart failure sedentary (H) group and heart failure exercise (HE) group. The animals in HE group underwent 10-week treadmill running, while those in S group and H group were sustained in a resting state. The cardiac structure and function including left ventricular internal diameter at diastole (LVIDd), left ventricular internal diameter at systole (LVIDs), left ventricular anterior wall diameter at diastole (LVAWDd), left ventricular anterior wall diameter at systole (LVAWDs), left ventricular posterior wall diameter at diastole (LVPWDd) and left ventricular posterior wall diameter at systole (LVPWDs), and cardiac function parameters including fractional shortening (FS) and left ventricular ejection fraction (LVEF) were measured by echocardiography. The myocardium was collected for histopathological observation with Masson staining, and the collagen volume fraction (CVF) was determined. The concentrations of norepinephrine (NE) in the myocardium and plasma were measured by high-pressure liquid chromatography. The frequency domain analysis was applied for determining the heart rate variability (HRV) via subcutaneous recording electrode involving total power (TP), normalized low power (LFn), normalized high power (HFn) and LF/HF ratio. The mRNA expression of collagen type I (Col-I), collagen type III (Col-III), atrial natriuretic factor (ANF), α-myosin heavy chain (α-MHC), β-myosin heavy chain (β-MHC), sarcoplasmic endoplasmic reticulum Ca²⁺-ATPase (SERCA2a) was detected by real-time PCR. The protein levels of nerve growth factor (NGF) and its receptor (TrkA), and tyrosine hydroxylase (TH) were measured by Western blotting. RESULTS: (1) Compared with S group, body weight (BW), LVIDd, FS, LVEF, TP, HFn, the mRNA expression of α-MHC and SERCA2a, and the protein levels of NGF, TrkA and TH decreased (P<0.05). Left ventricular weight (LVW), left ventricular mass index (LVMI), LVAWDd, LVAWDs, LVPWDd, LVPWDs, CVF, plasma and myocardial NE content, LFn, LF/HF, and the mRNA expression of ANF, β-MHC, Col-I and Col-III increased (P<0.05) in H group. (2) Compared with H group, LVW, LVMI, LVIDd, FS, LVEF, TP, HFn, the mRNA expression of α-MHC and SERCA2a, and the protein levels of NGF, TrkA and TH were raised (P<0.05), while CVF, plasma and myocardial NE content, LFn, LF/HF, and the mRNA expression of ANF, β-MHC, Col-I and Col-III decreased (P<0.05) in HE group. CONCLUSION: Long-term aerobic exercise training leads to inhibition of heart and sympathetic neural remodeling and improvement of cardiac function and autonomic modulation in the rats after myocardial infarction.     

Effect of chronic administration of L-thyroxine on Ca2+/calmodulin-dependent protein kinaseⅡ in rat myocardium

AIM: To investigate the effect of chronic injection of L-thyroxine on Ca²⁺/calmodulin-dependent protein kinaseⅡ (CaMKII) and to explore whether CaMKII directly mediates hyperthyroidism-induced cardiac hypertrophy. METHODS: Twenty male Sprague-Dawley rats were randomly divided into hyperthyroid group and control group with 10 animals each. The animal model was produced by intraperitoneal injection of L-thyroxine (0.2 mg·kg^-1·d^-1) for 3 months. The control animals only received saline vehicle in the same procedures. Heart weight (HW), heart-to-body weight ratio (HW/BW), left ventricular-to-body weight ratio (LVW/BW) and diameter of cardiac myocytes were measured to evaluate cardiac hypertrophy. The ratio of perivascular collagen area to vascular luminal area (PVCA/VA) was used to represent myocrdial fibrosis. Moreover, the mRNA expression of CaMKII and the protein level of CaMKII were measured by real-time RT-PCR and Western blotting, respectively. RESULTS: Intraperitoneal injection of L-thyroxine for 3 months significantly increased HW/BW, LVW/BW, PVCA/VA and diameter of cardiac myocytes by 1.87, 1.84, 1.94 and 2.15 folds, respectively (P<0.05 or P<0.01) as compared with control group. The results of real-time RT-PCR revealed that L-thyroxine injection caused a 60% reduction in the mRNA level of cardiac CaMKII (P<0.05). Furthermore, the results of Western blotting confirmed that the protein expression level of cardiac CaMKII in L-thyroxine group diminished by 21% (P<0.05), but accompanied by a 1.58-fold enhancement of phosphorylated activity of CaMKII (P<0.05). CONCLUSION: Thyroxine decreases the expression level of cardiac CaMKII and increases the activity of CaMKII in the chronic hyperthyroid-induced hypertrophic heart, suggesting that CaMKII participates in the formation and maintenance of cardiac hypertrophy induced by hyperthyroidism in a balanced way.     

Protective effects of total saponins of panax notoginseng on myocardial hypertrophy and fibrosis induced by isoproterenol in rats

AIM: To investigate the protective effects of total saponins of panax notoginseng (PNS) on myocardial hypertrophy and fibrosis induced by isoproterenol (ISO) in rats.METHODS: Myocardial hypertrophy and fibrosis model of rats were induced by injection of ISO (5 mg·kg^-1·d^-1,sc) for 7 days.From day 2,the rats were administered with PNS at dose of 25 and 50 mg·kg^-1·d^-1,ip for 14 days,the control and ISO model group were received saline injection.Then,the heart-weight (HW),left ventricular weight (LVW),the ratio of HW/BW and LVW/BW (LVI) were measured;the hydroxyproline and malondialdehyde (MDA) and angiotensin (AngII) content of left ventricle.The level of nitric oxide (NO),nitric oxide synthase (NOS),superoxide disrnutase (SOD) and glutathione peroxidase (GSH-Px) activities in left ventricle were determined by spectrophotemetry and radioimmunoassay,respectively.RESULTS: Compared with NS control group,the ratio of HW/BW,LVW/BW and the content of hydroxyproline,AngII,MDA and iNOS activity in the left ventricle were significantly increased.The cNOS,SOD,GSH-Px activities and NO content were obriously decreased in the ISO model group.After treatment with PNS,the left ventricular NO content,cNOS,SOD and GSH-Px activities were markedly higher than those in ISO model group.The content of MDA,AngII and iNOS activities and the ratio of HW/BW,LVI were significantly lower than those in ISO model group.CONCLUSION: PNS reverses the myocardial hypertrophy and fibrosis induced by isoproterenol in rats.This effect may be related to eliminating the oxygen free radicals and raising NO level.     

Role of bradykinin in the therapeutic effect of enalapril on left ventricular hypertrophy and cardiac function after myocardial infarction in rats

AIM:To investigate the influences of bradykinin(BK)on left ventricular hypertrophy and cardiac function in angiotensin-converting enzyme inhibitor(ACEI) therapy in rats after myocardial infarction.METHODS:The effects of enalapril (500 μg·kg^-1·d^-1), enalapril (500 μg·kg^-1·d^-1)with BKB₂ receptor antagonist (Hoe-140 500 μg·kg^-1·d^-1), losartan(3 mg·kg^-1·d^-1) on left ventricular end-diastolic pressure (LVEDP), maximum positive left ventricular pressure change (+dp/dt_max) and LVW/BW as well as V(m)n of noinfarcted area were examined after 4 weeks treatment in rats after myocardial infarction.RESULTS:The values of LVEDP, LVW/BW and V(m)n of three treatment groups were higher than that of untreated MI group (P＜0.05),but the +dp/dt_max of three treatment groups were not significantly different compared with the untreated MI group. In addition, no significant difference in MAP was observed among the three treatment groups, but the LVW/BW and V(m)n of enalapril+Hoe-140-treated group were higher than that of enalapril-treated group (P＜0.05) .CONCLUSION:Enalapril can prevent left ventricular hypertrophy and improve cardiac function independent of blood pressure after myocardial infarction, which is partly due to the inhibition of BK degradation.     

Effect of imatinib on myocardial fibrosis in DOCA-salt hypertensive rats

AIM: To investigate the effects of imatinib (IMA), one of platelet-derived growth factor receptor (PDGFR) inhibitors, on myocardial fibrosis in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. METHODS: Sixty male uninephrectomized SD rats were treated with 1% NaCl and 0.2% KCl in the drinking water for 4 weeks and assigned to 3 groups: vehicle control group (control group), DOCA treatment group (DOCA group), DOCA and IMA treatment group (DOCA+IMA group). Systolic blood pressure (SBP) was measured using the tail-cuff method. Myocardial tissue inflammation was analyzed by hematoxylin-eosin staining. Collagen volume fraction (CVF) and perivascular collagen area (PVCA) were analyzed by Sirius red staining. Ectodermal dysplasia-1 (ED-1) was analyzed by immunohistochemistry. Expression levels of platelet-derived growth factors (PDGF-A and PDGF-C), PDGF receptor α (PDGFRα) and phosphorylated PDGFRα (p-PDGFRα) were detected by Western blotting. RESULTS: SBP in DOCA group and DOCA+IMA group were signficantly higher than that in control group. No significant difference of SBP between DOCA group and DOCA+IM group was observed. In DOCA group, severe myocardial fibrosis was found, and CVF and PVCA were higher than those in control group. The differences of the CVF and PVCA between DOCA+IMA group and control group were detected, but the CVF and PVCA in DOCA+IMA group were significantly lower than those in DOCA group. Compared with control group, different degrees of myocardial tissue inflammation and monocyte/macrophage infiltration were observed in DOCA group and DOCA+IMA group. The expression levels of PDGF-A, PDGF-C and PDGFRα in DOCA group and DOCA+IMA group were much higher than those in control group, but the expression of p-PDGFRα in DOCA+IMA group were signficantly lower than that in DOCA group. CONCLUSION: Mineralocorticoid-induced myocardial fibrosis is related to cardiac tissue inflammatory response, excessive monocyte/macrophage infiltration and expressions of PDGF-A,PDGF-C and PDGFRα. Imatinib has an inhibitory effect on the myocardial fibrosis. The mechanisms may be associated with the inhibition of PDGFRα activity on the surface of fibroblast, thus interrupting PDGFs signaling-induced fibroblast division and proliferation.     

Effect of atorvastatin on myocardial fibrosis induced by aldosterone

AIM: To investigate the effects and mechanisms of atorvastatin on myocardial fibrosis induced by aldosterone in SD rats. METHODS: Forty male uninephrectomized SD rats were limited to drink 1% NaCl water for 4 weeks and assigned to the follow groups: vehicle control rats (CON group); aldosterone treated rats (ALD group); spironolactone + aldosterone treated rats (SPI+ALD group); atorvastatin + aldosterone treated rats (ATO+ALD group). Blood pressure was measured by catheterization. Expression of platelet-derived growth factor (PDGF-A, PDGF-B), platelet-derived growth factor receptor (PDGFR-α, PDGFR-β) and ectodermal dysplasia-1 (ED-1) were analyzed by immunohistochemistry. Collagen volume fraction (CVF) and perivascular collagen area (PVCA) were analyzed by Sirius-Red staining. Myocardium osteopontin protein was detected by Western blotting analysis. RESULTS: Mean arterial blood pressure in ALD group, SPI+ALD group and ATO+ALD group was elevated, and significant difference was observed between the three groups and vehicle control group (P<0.01 or P<0.05). Myocardial fibrosis was observed in ALD group. Compared to other three groups, the index of CVF and PVCA was increased significantly (P<0.01 or P<0.05). No significant difference of the index of CVF and PVCA between ATO+ALD group and SPI+ALD group was observed (P>0.05). Compared to other groups, the levels of PDGF-A, PDGF-B, PDGFR-α, ED-1 and OPN in ALD group were significantly increased (P<0.01 or P<0.05). The levels of PDGF-A, PDGF-B, PDGFR-α and OPN were no significant difference between ATO+ALD group and SPI+ALD group (P<0.01 or P<0.05). However, the level of ED-1 in ATO+ALD group was significantly decreased compared to SPI+ALD group (P<0.05). No significant difference of PDGFR-β level among four groups was found (P>0.05). CONCLUSION: These results suggest that atorvastatin may attenuate myocardial fibrosis induced by aldosterone. The mechanisms concern with reduction of macrophage infiltration, expression of inflammatory cytokines OPN, partially inhibition of platelet-derived growth factor and its receptor expression.     

Up-regulation of miR-133a expression attenuates myocardial fibrosis in spontaneously hypertensive rats

AIM: To investigate the effect of up-regulated expression of microRNA-133a (miR-133a) on myocardial fibrosis in spontaneously hypertensive rats (SHR). METHODS: Wistar-Kyoto (WKY) rats with homologous normal blood pressure served as the normal control group. SHR were divided into SHR group, SHR+ adeno-associated virus (AAV) group and SHR+miR-133a-AAV group randomly. miR-133a carried by miR-133a-AAV was transfected into SHR heart by coronary perfusion. The rat tail artery pressure was monitored. The myocardial collagen deposition was observed by Masson staining. The expression of miR-133a in myocardial tissue was detected by real-time PCR. The protein levels of transforming growth factor-β1 (TGF-β1) and connective tissue growth factor (CTGF) were determined by immunohistochemistry and Western blot. RESULTS: Compared with the WKY rats, the tail artery pressure of the SHR increased significantly. The expression of miR-133a in heart decreased, and the expression levels of TGF-β1 and CTGF increased (P<0.05), and myocardial fibrosis occurred. After up-regulating the expression level of miR-133a in the heart of SHR, the myocardial fibrosis was significantly reduced, and the expression levels of TGF-β1 and CTGF decreased (P<0.05). CONCLUSION: Up-regulation of the miR-133a expression improves myocardial fibrosis induced by hypertension, which may be related to inhibiting the protein expression of TGF-β1 and CTGF in myocardium.     

Effects of atorvastatin on myocardium expression of peroxisome proliferator-activated receptors in spontaneously hypertensive rats

AIM: To investigate the effects of atorvastatin on myocardium peroxisome proliferator-activated receptors (PPARs) expression, regression of left ventricular hypertrophy, and the possible mechanisms in spontaneously hypertensive rats (SHR). METHODS: 16 nine-week-old male spontaneously hypertensive rats were randomly divided into two groups: SHR received atorvastatin at dose of 30 mg·kg-1·d-1 by oral gavage once daily for 8 weeks (SHR-A, n=8), and SHR received vehicle (0.9% saline) as controls (SHR, n=8). Age-matched Wistar-kyoto rats received vehicle for 8 weeks were served as normaltensive controls (WKY, n=8). Systolic blood pressure was measured at the beginning, 2, 4 and 8 weeks of the experiment. At the end of the experiment, plasma lipid levels were measured. Left ventricular hypertrophy was accessed by pathological analysis. The expressions of PPARα and PPARγ were investigated by the method of Western blotting. RESULTS: There was not much difference of systolic blood pressure and plasma lipid levels between SHR-A and SHR group (P>0.05). Compared with SHR group, left ventricular weight mass index decreased significantly in SHR-A group (P<0.01). The myocardium PPARα and PPARγ expression increased significantly (P<0.01). CONCLUSION: Atorvastatin regresses left ventricular hypertrophy and increases myocardium PPARα and PPARγ expression in spontaneously hypertensive rats, which is independent of its lipid-lowering activity.     

Effects of rAAV9-mediated siRNA for p65 knockdown on myocardial fibrosis and apoptosis in rats with pressure overload

AIM To investigate the effect of p65 gene knock-down mediated by recombinant adeno-associated virus serotype 9 （rAAV9） on the cardiac function of pressure overload rat and its possible mechanism. METHODS The rat model of left ventricular hypertrophy was established by abdominal aortic coarctation（AAC）. SD rats were randomly divided into sham operation group， AAC group， AAC+rAAV9-eGFP group and AAC+rAAV9-eGFP-P65-siRNA group. The abdominal cavity was closed directly after laparotomy in the rats of sham operation group， the abdominal cavity was closed after ligation of the abdominal aorta in the rats of AAC group， and normal saline， rAAV9-eGFP and rAAV9-eGFP-P65-siRNA were injected into the tail vein 3 d after operation. After 4 weeks， the hemodynamic indexes were measured， the heart mass parameters were calculated， the degree of myocardial fibrosis was detected by Masson staining， the expression level of myocardial P65 was detected by Western blot， the degree of apoptosis was detected by TUNEL staining， and the serum contents of tumor necrosis factor-α （TNF-α） and interleukin-6 （IL-6） of the rats in each group were measured by ELISA. RESULTS The expression of P65 in AAC group and AAC+rAAV9-eGFP group was higher than that in sham operation group， while the expression of P65 in AAC+rAAV9-eGFP-P65-siRNA group was significantly lower than that in AAC group. The levels of systolic blood prossure （SBP）， diastolic blood pressure （DBP）， left ventricular weight/body weight （LVW/BW）， cardiomyocyte apoptotic rate and TNF- α and IL-6 in AAC group and AAC+rAAV9-eGFP group were higher than those in sham operation group， while SBP， DBP， LVW/BW， cardiomyocyte apoptosis rate and TNF-α in AAC+rAAV9-eGFP-P65-siRNA group were significantly lower than those in AAC group. The results of Masson staining showed that the deposition of collagen in cardiac tissue in AAC group and AAC+rAAV9-eGFP group was higher than that in sham operation group， and treatment with rAAV9-eGFP-P65-siRNA alleviated hypertension-induced fibrosis. CONCLUSION Knockdown of p65 gene reduces the degree of left ventricular fibrosis and apoptosis in rats with stress overload， and its mechanism is related to the regulation of NF-κB pathway and the reduction of inflammatory response.     

Effects of valsartan alone or in combination with benazepril on blood pressure and left ventricular hypertrophy in spontaneously hypertensive rats

AIM:To evaluate the effects of different doses of valsartan alone or with concomitant be-nazepril on blood pressure,left ventricular hypertrophy,RAASfunction and endoxi nlevel in spontaneously hy-pertensive rats(SHR).METHODS:Thirty SHR(fourteen-week-old,male)were divi ded into five groups(six rats in each group):SHR control group:fed with normal saline;benazepril group:fed with 1 mg·kg^-1·d^-1benazepril);low dose valsartan group:fed with 8 mg·kg^-1·d^-1valsartan;high dose valsartan group:fed with 24 mg·kg^-1·d^-1valsartan;combination drug therapy group:fed with valsartan(8 mg·kg^-1·d^-1)and benazepril(1 mg·kg^-1·d^-1),all for 8 weeks.WKY control group(n=6):fed with normal saline for 8 weeks.RESULTS:SBP,LVM/BW,TDMof SHR were remarkably lower than those of control after drug i n-tervene,and effect on SBP was most remarkable in high dose valsartan group and i nthe combi nation drug ther-apy group;effect on LVM/BW,TDM were most remarkable in combination drug therapy group.Renin activi-ties in plasma and myocardiumwere remarkably i ncreased in drug i ntervene groups.The levels of AngⅡi nplasma and myocardiumwere remarkably increased in two different dose of valsartan treati ng group,and thelarger dose of valsartan were,the higher levels of AngⅡin plasma and myocardium were;decreased in be-nazepril treati ng group and combination drug therapy group.Na⁺-K⁺-ATPase activities in myocardi umwere remarkably i ncreased and the level of endoxi n i n myocardium were remarkably decreased as SBP de-creased after drug intervene.CONCLUSION:Different dose of valsartan alone or combi ned with benazeprilcan decrease SBP of SHR,have the effect of inhibiti ng progression of ventricular hypertrophy.The effect ofcombination drug therapy group was most remarkable among five groups and can avoi d the si de effect of highAngⅡin plasma and myocardiumduri ng long-termuse of valsartan alone.     

Effect of rhynchophylline on TGF-β1/Smad pathway for processing ventricular remodeling in spontaneously hypertensive rats

AIM: To investigate the effect of rhynchophylline (Rhy) on blood pressure, cardiac hypertrophy and myocardial fibrosis in spontaneously hypertensive rats (SHR). METHODS: Spontaneously hypertensive rats were randomly divided into model group, high dose (10 mg·kg^-1·d^-1) and low dose (2.5 mg·kg^-1·d^-1) group of rhynchophylline, captopril group (17.5 mg·kg^-1·d^-1). Wistar-Kyoto rats were used as normal control. Respectively, systolic blood pressure was measured by tail cuff every 2 weeks. After 10 weeks, heart weight index and left ventricular weight index were calculated. The myocardial hydroxyproline and plasma angiotensin Ⅱ were detected. Moreover, basic myocardial histopathological changes and myocardial collagen fibres were observed by HE staining and Masson staining, respectively. The protein expression of TGF-β₁ and Smad3 in the myocardium was measured by the methods of immunohistochemistry and Western blot. RESULTS: Compared with SHR model group, Rhy significantly reduced blood pressure (P<0.05), the levels of HYP in the myocardium (P<0.05) and the levels of AngⅡ in the plasma (P<0.01). The pathological damages of the myocardial tissues and collagen deposition were attenuated. The protein expression of TGF-β₁ and Smad3 was significantly reduced by the treatment with Rhy (P<0.01). CONCLUSION: Rhynchophylline reduces blood pressure and adjusts to improve ventricular remodeling of SHR. The mechanism may be involved in the TGF-β₁/Smad pathway and reducing AngⅡ content.     

Zacopride attenuates pressure overload-induced ventricular remodeling in rats

AIM:To investigate the protective effect of zacopride (ZAC) on the pressure-overload left ventricular remodeling in the rats induced by coarctation of abdominal aorta. METHODS:Male Sprague-Dawley (SD) rats with pressure overload were induced by the coarctation of abdominal aorta. The model rats were intraperitoneally administered with ZAC, chloroquine (Chlor), and zacopride+chlorquine (ZAC+Chlor). The study duration was 8 weeks. The cardiac structure and function were assessed by echocardiography. The heart weight/body weight (HW/BW) ratio and the left ventricular weight/body weight (LVW/BW) ratio were calculated. The changes of structure and shape in myocardial tissue were observed with HE staining. The ultrastructure of the myocytes was observed under transmission electron microscope. The inward rectifier potassium channel (I_K1) protein expression was determined by Western blot. The mRNA expression of Kir2.1 was detected by RT-PCR. RESULTS:Compared with vehicle group, ZAC improved cardiac function, as indicated by the decreased left ventricular end-diastolic dimension (LVEDD) and left ventricular end systolic dimension (LVESD) (P<0.05), and the increased left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) (P<0.01). The HW/BW and LVW/BW ratios were significantly decreased, and the cross-sectional area of the cardiomyocytes was significantly less in ZAC group than that in vehicle group (P<0.01). The ultrastructure of the myocytes was significantly improved. Chlor blocked the protective effect of zacopride on the pressure-overload left ventricular remodeling. The protein level of I_K1 and mRNA expression of Kir2.1 in the cardiac tissues in ZAC group were significantly increased compared with vehicle group (P<0.01). CONCLUSION:I_K1 agonist ZAC significantly attenuates pressure overload-induced ventricular remodeling in rats.     

Relationship between the intracellular calcium concentration changes and left ventricular hypertrophy and function in the spontaneously hypertensive rats

AIM:To elucidate the relationship between the intracellular calcium concentration changes and left ventricular hypertrophy and function in the spontaneously hypertensive rats (SHR).METHODS:Intracellular free calcium concentrations were measured by Fura 2 methodology and left ventricular function quantitated by cardiac catheterization in 20 SHR aged 10, 22, and 34 weeks and 20 age-matched Wistar-kyoto (WKY) rats.RESULTS:(1) The systolic blood pressure(SBP), intracellular calcium concentrations and left ventricular mass / body weight index (LVM/BW) were significantly higher in all three age groups of SHR than the corresponding groups of WKY; (2) Compared with age-matched WKY groups, the peak left ventricular pressure descending rate(-dp／dt_max) decreased while left ventricular relaxation time constant (τ)increased significantly in SHR aged 22 and 34 weeks. The peak left ventricular pressure ascending rate(dp／dt_max) and the left ventricular contractility index were significantly increased only in the 34 weeks SHR; (3) Intracellular calcium concentrations showed a positive correlation with LVM/BW,SBP,-dp／dt_max and τ(r=0.47-0.83,P<0.01)and a negative correlation with dp／dt_max and the left ventricular contractility index (r=-0.46,P<0.05 and r=-0.81, P<0.01).CONCLUSION:Intracellular calcium overload is one of the potential mechanisms in the induction of left ventricular hypertrophy as well as of systolic and diastolic dysfunction.     

Role of benazepril on extracellular signal-regulated kinase activity and expression of B-type natriuretic peptide in spontaneously hypertensive rats

AIM：To investigate the role of benazepril on extracellular signal-regulated kinase (ERK) activity and expression of B-type natriuretic peptide in spontaneously hypertension rat (SHR).METHODS：Wistar Kyoto rats were used as control group.Twenty one 14-week-age SHR were randomized into 3 groups,7 rats each：benazepril group (10 mg·kg-1·d-1);hydralazine group (10 mg·kg-1·d-1) and sham group.In each group drugs or equal volume of vehicle (0.5% carboxymethyl cellulose) were administered respectively for 10 weeks by gavage.The ratio of left ventricle weight to body weight （LVW/BW） was measured to reflect myocardial hypertrophy.The caudal arterial pressure was measured by tail-cuff.Protein expression of p-ERK in myocardial tissue was detected by Western blotting,BNP mRNA in myocardial tissue was examined by RT-PCR,and protein expression of plasma BNP was detected by ELISA.RESULTS：1.Benazepril and hydralazine lowered the blood pressure after 10 weeks treatment (P<0.01).2.The ratio of LVW/BW in SHR benazepril group was significantly lower than that in SHR hydralazine group and SHR sham group (P<0.01),and similar to that in WKY group (P>0.05).3.The protein expression of p-ERK in myocardial tissue in SHR benazepril group was significantly lower than that in SHR hydralazine group and SHR sham group (P<0.01),and similar to that in WKY group (P>0.05).There was no significant difference of p-ERK expression between SHR hydralazine group and SHR sham group (P>0.05).4.The levels of plasma BNP and BNP mRNA in myocardial tissue in SHR benazepril group were significantly lower than that in SHR hydralazine group and SHR sham group (P<0.01),and similar to that in WKY group (P>0.05).There was no significant difference of plasma BNP and BNP mRNA in myocardial tissue between SHR hydralazine group and SHR sham group (P>0.05).CONCLUSIONS：Benazepril inhibited ERK activation,resulting in regression of myocardial hypertrophy and accompanied by the reduction of BNP level.However,in spite of the effect of lowering blood pressure,hydralazine did not prevent or regress cardiac hypertrophy and did not decrease the level of p-ERK and BNP in SHR.BNP level might serve as a therapeutic index for reversal of myocardial hypertrophy.     

Effects of fluvastatin on the left ventricular function,MHC gene expression and collagen remodeling after myocardial infarction

AIM: To observe the effects of fluvastatin (FV) on the left ventricular (LV) function, MHC mRNA and collagen remodeling of non-infarcted area after acute myocardial infarction (AMI). METHODS: Six hours after ligating left coronary artery, survivors of AMI female SD rats were randomly assigned to: ①AMI control; ②FV; ③sham-operated groups. After 8 weeks of therapy, the LV function, hemodynamics, expression of non-infarcted myocardial MHC mRNA, collagen volume fraction (CVF) and the ratio of type Ⅰ/Ⅲ collagen of non-infarcted area were assessed. RESULTS: Compared with sham-operated group, E wave, E wave deceleration, E/A ratio, LV end diastolic pressure (LVEDP), β MHC mRNA, CVF and the ratio of type Ⅰ/Ⅲ collagen were all significantly increased in AMI group, while fractional shortening (FS), ejection fraction (EF), mean arterial pressure (MAP) and α MHC mRNA were all significantly decreased. In comparison with AMI group, E wave, E wave deceleration, E/A, LVEDP, β MHC mRNA, CVF and the ratio of type Ⅰ/Ⅲ collagen were all significantly decreased, while FS, EF, MAP and α MHC mRNA were all significantly increased in FV group. CONCLUSION: FV improves the LV function after AMI and has beneficial effects on reversing LV myocardial pathologic switching of MHC isoform and collagen remodeling.     

Long-term effects of TCV116 on left ventricular remodeling and heart function after myocardial infarction in rats

AIM: To investigate the effects of long-term TCV116 on left ventricular remodeling and heart function after myocardial infarction. METHODS: Myocardial infarction (MI) was caused by ligation of the left anterior descending coronary artery in rats. One week after the surgical performance, the surviving rats were randomly assigned to the following treatment protocols: (1) MI rats with no therapy; (2) MI rats treated with TCV116 2 mg/kg per day; (3) Sham-operated control; (4) Sham-operated rats, treated with TCV116 2 mg/kg per day. At 22 weeks, cardiac hemodynamic parameters such as MAP, LVSP, dp/dt_max and LVEDP, and histomorphometric parameters such as LVW/BW and LVCA/BW were measured, mRNA of cardiac genes such as βMHC, BNP, TGF-β₁, collagen I and III were quantified, and survival rates were calculated. RESULTS: Compared with sham-operated rats, MI rats without therapy showed significant increases in histomorphometric parameters as well as in mRAN expressions of cardiac genes (P<0.01); While their hemodynamic parameters were significantly impaired (P<0.01), and survival duration shortened (P<0.05). Compared with MI rats without therapy, MI rats treated with TCV116 showed significant attenuation of mRAN expression of cardiac genes (P<0.01); While their hemodynamic parameters were significantly improved (P<0.05 or P＜0.01), and survival duration extended (P<0.05). CONCLUSION: Treatment with long-term angiotensin II type 1 receptor antagonist may improve left ventricular remodeling and cardiac function after MI in rats.