Determination of perindopril erbumine by oxidative coupling reaction using 2, 6-dichloroquinone-4-chlorimide

Abstract Perindopril erbumine (Perindopril tert-butylamine salt) is a potent angiotensin-converting enzyme (ACE) inhibitor. It is used to treat the patients with hypertension and heart failure problems. A sensitive, inexpensive and precise analytical technique has been developed for the estimation of perindopril in bulk and formulations. The procedure involves the development of colour by forming an oxidative coupling reaction between drug (PPE) and reagent such as 2, 6-dichloroquinone-4-chlorimide (DCQC). The formed colored species were measured at (max=520 nm. The developed method showed linearity within the concentration limits of 25-75 µg mL-1. The linear correlation coefficient (r) and molar absorptivity were found to be 0.9999 and 3.285 x 103 mol-1cm-1. % Recovery ± SD values were in the range of 99.69 - 100.51 (+ 0.42 - ( 0.41) (n=3) which indicates the accuracy of the developed method. The interference of other excipients that are commonly present in formulations is found to be negligible. Precision and accuracy of the proposed method were confirmed by student t-test and F-tests at 95% confidence limits with (n-1) degrees of freedom. The validity parameters of proposed method were calculated by ICH guidelines

Investigation on the role on perindopril for prevention and treatment of glucocorticoid-induced osteoporosis in rabbits / 中国骨伤

<p><b>OBJECTIVE</b>To investigate the role of perindopril for prevention and treatment of glucocorticoid-induced osteoporosis (GIOP) in rabbits.</p><p><b>METHODS</b>A total of 45 male New Zealand white rabbits (10 months old, weight 3.0 to 3.5 kg) were randomly divided into 3 groups involving normal control group (muscle injection of saline solution, n = 15, group NC), model group (muscle injection of dexamethasone, n = 15, group GIOP), and treatment group (muscle injection of dexamethasone combined with oral perindopril, n = 15, group GIOP+ACEI). All rabbits put to death after 12 weeks' treatment. The changes of bone mass and strength were observed and analyzed by bone histomorphology, biomechanics, metabolic bone related serological indexes and mRNA expression.</p><p><b>RESULTS</b>At 12 weeks, the analysis of bone histomorphology and biomechanics results showed that the bone mass and bone strength of group GIOP were significantly lower than that of group NC (P < 0.05); after perindopril treatment, the bone mass and bone strength of group GIOP+ACEI were higher obviously than that of group GIOP (P < 0.05). Mineralizing surface,mineral apposition rate and serum osteocalcin in group GIOP decreased than group NC; however, osteoclast number, osteoclast surface, eroded surface, and urinary deoxypyridinoline in group GIOP increased than group NC (P < 0.05); these changes were inhibited after perindopril treatment (P < 0.05). Quantitative RT-PCR revealed that after dexamethasone treatment, the ratio of SOST mRNS expression and RANKL/OPG mRNA expression obviously increased than that of group NC (P < 0.05); and Runx2 expression decreased significantly (P < 0.05); while the changes of mRNA expression were improved by perindopril treatment.</p><p><b>CONCLUSION</b>Perindopril can promote bone formation and inhibit bone resorption to deduce glucocorticoid-induced osteoporosis. This study provides a new method for prevention and treatment of GIOP.</p>

Efficacy comparison between 5 mg perindopril arginine salt and 4 mg perindopril tert-butylamine salt for patients with mild to moderate essential hypertension / 中华心血管病杂志

<p><b>OBJECTIVE</b>To compare the efficacy and safety of 5 mg perindopril arginine salt and 4 mg perindopril tert-butylamine salt for patients with mild to moderate essential hypertension.</p><p><b>METHODS</b>The study was designed as multicenter, randomized, double-blind, active controlled trial with two parallel groups enrolling 524 participants with mild to moderate essential hypertension. After 2-week run-in period, 186 patients were enrolled and randomly treated with 5 mg perindopril arginine salt and 183 patients were enrolled and randomly treated with 4 mg perindopril tert-butylamine salt. The random sequence was generated by the I.R.I.S., and a balance was made in each center. After double-blind treatment for 8 weeks, the dose could be doubled for patients with uncontrolled BP ((SBP) ≥ 140 mmHg (1 mmHg = 0.133 kPa) or diastolic blood pressure (DBP) ≥ 90 mmHg) and patients were treated for another 4 weeks.</p><p><b>RESULTS</b>The sitting SBP was similarly decreased by (19.9 ± 17.2) mmHg in perindopril arginine group and (18.5 ± 14.7) mmHg (P = 0.000 5) in perindopril tert-butylamine group post 8 weeks treatment. Dose was doubled in 109 patients (59.9%) in perindopril arginine group and 116 patients (63.7%) in perindopril tert-butylamine group. At 12 weeks post therapy, the sitting SBP decreased by (19.8 ± 16.2) and (19.6 ± 16.3) mmHg respectively in the 2 groups. The decrease of sitting DBP was also similar in both groups (-12.0 ± 10.0) mmHg and (-11.0 ± 8.9) mmHg (P < 0.000 1), respectively. The control rate or response rate was also similar between the two groups (control rate over 8 weeks was 38.5% vs. 31.3%, 95% CI (-2.6-16.9), control rate over 12 weeks was 36.3% vs. 35.7%, 95% CI (-9.3-10.4), response rate over 8 weeks was 64.3% vs. 63.2%, 95% CI (-8.8-11.0), response rate over 12 weeks was 65.9% vs. 64.8%, 95% CI (-8.7-10.9)). Incidence of adverse events was low and similar in both therapy groups.</p><p><b>CONCLUSIONS</b>The results show that perindopril arginine salt 5 mg is as efficient as perindopril tert-butylamine 4 mg on lowering BP for patients with mild to moderate essential hypertension. Both drugs have good safety profile and are well tolerated by patients in this cohort.</p>

A Case of Pleural Effusion and Pulmonary Edema Caused by Calcium Channel Blockers in a Patient of Systemic Hypertension

Calcium channel blockers (CCBs) are very popular drugs to lower blood pressure (BP) without significant side effects. A 72-year-old man admitted for uncontrolled hypertension. He had history of hypertension, atrial fibrillation with slow ventricular response, angina, abdominal aortic aneurysm, and stage 3 chronic kidney disease. He had taken several anti-hypertensives, such as amlodipine 5 mg, perindopril 8 mg, and indepamide 1.5 mg. To control BP, nifedipine 120 mg was added. Then pulmonary edema and pleural effusion was developed. Echocardiography showed preserved left ventricular ejection fraction and mild mitral regurgitation. Fluid restriction and high dose furosemide did not cease pleural fluid accumulation. Thus a total of 4 times of thoracentesis were done and all fluid analyses revealed transudate. We thought that pleural effusion and pulmonary edema was induced by CCBs and discontinued the drugs. He recovered quickly and finally discharged in a stable condition.

Cardioprotective Effect of Fimasartan, a New Angiotensin Receptor Blocker, in a Porcine Model of Acute Myocardial Infarction

Cardioprotective effect of fimasartan, a new angiotensin receptor blocker (ARB), was evaluated in a porcine model of acute myocardial infarction (MI). Fifty swine were randomized to group 1 (sham, n=10), group 2 (no angiotensin-converting enzyme inhibitor [ACEI] or ARB, n=10), group 3 (perindopril 2 mg daily, n=10), group 4 (valsartan 40 mg daily, n=10), or group 5 (fimasartan 30 mg daily, n=10). Acute MI was induced by occlusion of the left anterior descending artery for 50 min. Echocardiography, single photon emission computed tomography (SPECT), and F-18 fluorodeoxyglucose cardiac positron emission tomography (PET) were performed at baseline, 1 week, and 4 weeks. Iodine-123 meta-iodobenzylguanidine (MIBG) scan was done at 6 weeks for visualization of cardiac sympathetic activity. Left ventricular function and volumes at 4 weeks were similar between the 5 groups. No difference was observed in groups 2 to 5 in SPECT perfusion defect, matched and mismatched segments between SPECT and PET at 1 week and 4 weeks. MIBG scan showed similar uptake between the 5 groups. Pathologic analysis showed similar infarct size in groups 2 to 5. Infarct size reduction was not observed with use of fimasartan as well as other ACEI and ARB in a porcine model of acute MI.

Importância da proteção cardiovascular durante o tratamento da hipertensão arterial: diferenças entre os agentes inibidores do sistema renina-angiotensina-aldosterona / Importance of cardiovascular protection during arterial hypertension treatment: differences among renin-angiotensin-aldosterone system inhibitors

A inibição do sistema renina-angiotensina-aldosterona (SRAA) demonstrou ser fundamental não somente no controle da hipertensão arterial, mas também na redução da progressão de doenças cardíacas, renais e vasculares, com impacto positivo na morbimortalidade. Diversas evidências revelam que o SRAA participa ativamente da origem da hipertensão arterial, com relação no desenvolvimento de obesidade, dislipidemia, resistência à insulina e doença crônica renal, além de ser o responsável pela homeostase eletrolítica. A ativação do SRAA se associa com níveis elevados de enzima conversora de angiotensina (ECA) e expressão aumentada de angiotensinogênio, fatores esses que levam ao aumento de angiotensina II, responsável por estresse oxidativo, vasoconstrição, hiperatividade do sistema nervoso simpático e aumento da reabsorção de sódio. O SRAA pode ser inibido em diferentes estágios e por mecanismos diversos, sendo que a forma como é inibido tem influência no prognóstico. E, dentre essas opções, há evidências claras do melhor benefício sobre a redução da mortalidade por todas as causas e da mortalidade cardiovascular com o uso dos inibidores da ECA (IECA) sobre os bloqueadores de receptores AT1 (BRA). Dentre os diferentes IECA, o perindopril, através de suas características específicas e benefícios clínicos comprovados em estudos randomizados de maior impacto, garante uma superioridade na proteção cardiovascular durante o tratamento dos pacientes hipertensos. Cabe destacar que os estudos que deram origem aos IECA tiveram a participação de pesquisadores brasileiros, com destaque para o Professor Sérgio Ferreira (Hospital das Clínicas da Universidade de São Paulo, Ribeirão Preto)

Renin-angiotensin-aldosterone system (RAAS) inhibition has demonstrated to be crucial not only to control arterial hypertension but also to reduce the progression of cardiac, renal and vascular diseases, with positive impact on morbidity-mortality. There is evidence revealing that RAAS participates actively on arterial hypertension origin, also taking part on obesity, dyslipidemia, insulin resistance and chronic renal disease, besides being responsible for electrolytic homeostasis. RAAS activation is associated with elevated levels of angiotensin conversion enzyme (ACE) and angiotensinogen overexpression, factors which increase angiotensin II, that induces oxidative stress, vasoconstriction, sympathy nervous systemhyperactivity and sodium reabsorption increase. RAAS may be inhibited in different stages and through different mechanisms, and the way it is inhibited is linked to prognosis. Among available options, there is clear evidence of a better benefit over all cause and cardiovascular mortality reduction when using ACE inhibitors (ACEI) over AT1 receptor blockers (ARB). Among different ACEI, perindopril, through its specific characteristics and clinical benefits proved on high level randomized trials guarantees a superior cardiovascular protection while treating hypertensive subjects. It's nice to highlight that Brazilian researches, mainly Professor Sérgio Ferreira (Hospital das Clínicas da Universidade de São Paulo, Ribeirão Preto), took part on the studies that discovered ACEIs.

Effects of ACE inhibition on endothelial progenitor cell mobilization and prognosis after acute myocardial infarction in type 2 diabetic patients

OBJECTIVE: We aimed to assess the chemotactic response of endothelial progenitor cells to angiotensin-converting enzyme inhibitors in T2DM patients after acute myocardial infarction, as well as the associated prognosis. METHODS: Sixty-eight T2DM patients with acute myocardial infarction were randomized to either receive or not receive daily oral perindopril 4 mg, and 36 non-diabetic patients with acute myocardial infarction were enrolled as controls. The numbers of circulating CD45−/low+CD34+CD133+KDR+ endothelial progenitor cells, as well as the stromal cell-derived factor-α and high-sensitivity C reactive protein levels, were measured before acute percutaneous coronary intervention and on days 1, 3, 5, 7, 14, and 28 after percutaneous coronary intervention. Patients were followed up for 6 months. Chinese Clinical Trial Registry: ChiCTR-TRC-12002599. RESULTS: T2DM patients had lower circulating endothelial progenitor cell counts, decreased plasma vascular endothelial growth factor and α levels, and higher plasma high-sensitivity C reactive protein levels compared with non-diabetic controls. After receiving perindopril, the number of circulating endothelial progenitor cells increased from day 3 to 7, as did the plasma levels of vascular endothelial growth factor and stromal cell-derived factor-α, compared with the levels in T2DM controls. Plasma high-sensitivity C reactive protein levels in the treated group decreased to the same levels as those in non-diabetic controls. Furthermore, compared with T2DM controls, the perindopril-treated T2DM patients had lower cardiovascular mortality and occurrence of heart failure symptoms (p<0.05) and better left ventricle function (p<0.01). CONCLUSIONS: The use of angiotensin-converting enzyme inhibitors represents a novel approach for improving cardiovascular repair after acute myocardial infarction in T2DM patients. .

Effects of perindopril on expression of kidney aquaporin-2 and urine aquaporin-2 excretion in chronic heart failure rats / 中华心血管病杂志

<p><b>OBJECTIVE</b>To determine the expression of kidney aquaporin-2 (AQP2) and urine AQP2 excretion in chronic heart failure (CHF) rats and investigate effects of perindopril on the expression and excretion of AQP2.</p><p><b>METHODS</b>Sixty rats were randomized into three groups: control group, CHF group, CHF + Perindopril group. According to left ventricular myocardial infarction size, CHF group and perindopril group were further divided into heart failure subgroup (LVMI ≥ 20%) and cardiac functional compensation subgroup (LVMI < 20%), respectively. Blood and urine samples were collected from the rats for measuring serum Na(+), urine volume and urine osmolality. The concentration of plasma arginine vasopressin (p-AVP) was detected by radioimmunoassay (RIA). Immunohistochemistry, semi-quantitative real time-polymerase chain reaction (RT-PCR) and Western blot were performed for measurement of kidney inner medullary AQP2. The concentration of Urine AQP2 was measured by indirect enzyme-linked immunosorbent assay (indirect ELISA).</p><p><b>RESULTS</b>Immunohistochemistry, RT-PCR, Western blot examinations revealed increased quantity of the inner kidney medullary AQP2 expression (0.2013 ± 0.0417), AQP2 mRNA (0.98 ± 0.33) and AQP2 protein expression (0.94 ± 0.21) in heart failure subgroup (n = 13) compared to control group (n = 20, 0.1518 ± 0.0214, 0.58 ± 0.51, 0.51 ± 0.46), which could be significantly by perindopril (n = 13, 0.0712 ± 0.0218, 0.76 ± 0.45, 0.82 ± 0.49, all P < 0.05 vs. heart failure subgroup). The concentration of plasma arginine AVP [(19.72 ± 3.91) ng/ml] and Urine AQP2 [(82.52 ± 11.77) ng/L] were significantly higher in heart failure subgroup than in control group [n = 20, (51.67 ± 12.58) ng/L, (6.94 ± 3.10) ng/ml] (P < 0.05), which were significantly reduced by perindopril [n = 13, (15.65 ± 4.10) ng/L, (71.65 ± 9.21) ng/ml].</p><p><b>CONCLUSION</b>Increased expression of the kidney inner medullary AQP2 and the excretion of urine AQP2 in chronic heart failure rats could be reduced by perindopril.</p>

Effect of different doses of perindopril on myocardial energy expenditure in patients with heart failure following myocardial infarction / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate the changes of myocardial energy expenditure in patients with heart failure following myocardial infarction after treatment with different doses of perindopril.</p><p><b>METHODS</b>Sixty-three patients with heart failure after myocardial infarction were treated with perindopril for 12 months at the doses of 4 mg (group N) and 8 mg (group H). Doppler imaging was used to measure the structural and systolic functional parameters before and after the treatment, and the circumferential end-systolic wall stress (cESS) and myocardial energy expenditure (MEE) were calculated. The biochemical indicators including serum creatinine and plasma NT-proBNP were detected before and after the treatment.</p><p><b>RESULTS</b>The two groups had similar measurements before treatment. After 12 months of perindopril treatment, the patients in group N showed higher LA, LV, RA, RV, LVIDs, AD, cESS, lgNT-proBNP, and MEE with lower LVFS and LVEF than those in group H. Compared to those before treatment, LVFS and LVEF were increased and LA, LV, RA, RV, AD, LVIDs, LVMI, lgNT-proBNP and MEEm lowered after the 12-month treatment in group H. Significant changes were also found in the measured parameters except for PWTs, LVET, LVSV and LVFS in group N after the treatment. Bivariate analysis showed a significant positive correlation between MEE and lgNT-proBNP (r=0.513, P<0.01).</p><p><b>CONCLUSION</b>A 12-month treatment with perindopril can suppress myocardial remodeling, improve left ventricular systolic function, and lower NT-proBNP and myocardial energy expenditure in patients with heart failure after myocardial infarction, and a higher dose can produce better results.</p>

Perindopril and losartan attenuate intrahepatic Toll-like receptor 4 protein expression in rats with bile duct ligation-induced hepatic fibrosis / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate the expression of Toll-like receptor 4 (TLR4) in the liver tissue of rats with bile duct ligation (BDL)-induced hepatic fibrosis and evaluate the inhibitory effects of perindopril and losartan on TLR4 expression.</p><p><b>METHODS</b>Male Wistar Rats were randomly divided into sham-operated group (n=6), BDL group, perindopril treatment group (2 mg/kg) and losartan treatment group (50 mg/kg) (n=12). Perindopril and losartan groups were further divided into two subgroups for corresponding treatments by gastric lavage once daily for 14 and 30 days. The protein level of TLR4 in the liver tissue was examined by Western blotting.</p><p><b>RESULTS</b>In 14-day BDL group, the protein level of TLR4 significantly increased to 6.53∓1.11 folds of that in the sham group (P<0.05), and was lowered significantly to 1.71∓0.41 folds and 0.95∓0.38 folds following perindopril and losartan treatments for 14 days. TLR4 expression significantly increased to 6.51∓0.87 folds and 5.64∓0.87 folds of that of the sham group in perindopril and losartan groups after the 30-day treatments (P<0.05).</p><p><b>CONCLUSION</b>TLR4 expression is up-regulated in the liver of rats with BDL-induced hepatic fibrosis, and can be lowered by perindopril and losartan treatmemts for 14 days.</p>

Regulation of Glucose Control in People with Type 2 Diabetes: A Review and Consensus / 당뇨병

A conference was convened by the Korean Diabetes Association and the Korean Endocrine Society on September 7, 2009 to discuss and organize the results of research on intensive glucose control for the prevention of cardiovascular disease in patients with type 2 diabetes. Professor Kyung Soo Park led the conference, and Professors Kwang Won Kim and Ho Young Son acted as chairmen. Professors Doo Man Kim, Tae Sun Park, and Bong Soo Cha reported on intensive glucose control and diabetic complications, including the UK Prospective Diabetes Study (UKPDS), Diabetes Control and Complication Trial (DCCT) research results, the recently published Action to Control Cardiovascular Risk in Diabetes (ACCORD), Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE), and Veterans Affairs Diabetes Trial (VADT) research, as well as meta-analyses. Professor Jeong-Taek Woo reported on the manuscript written by the committee for the Korean Diabetes Association which dealt with the treatment of diabetes mellitus. Professors Kyung Soo Ko, Joong Yeol Park, Hyun Shik Son, Moon-Kyu Lee, Dong-Won Byun, and Yoon-Sok Chung participated in the discussion and collected information for the manuscript from all of the participants. The aim of the debate was to determine how to establish target goals for intensive glucose control and how to individualize those goals. The participants concluded that there was no need to modify the recommendation of maintaining an HbA1c under 6.5%, the current blood glucose treatment goal that is recommended by the Korean Diabetes Association. In addition, individual target goals for glucose control were recommended depending on the situation of each patient. We report on the consensus statement from the meeting.

Regulation of Glucose Control in People with Type 2 Diabetes: A Review and Consensus / 당뇨병

A conference was convened by the Korean Diabetes Association and the Korean Endocrine Society on September 7, 2009 to discuss and organize the results of research on intensive glucose control for the prevention of cardiovascular disease in patients with type 2 diabetes. Professor Kyung Soo Park led the conference, and Professors Kwang Won Kim and Ho Young Son acted as chairmen. Professors Doo Man Kim, Tae Sun Park, and Bong Soo Cha reported on intensive glucose control and diabetic complications, including the UK Prospective Diabetes Study (UKPDS), Diabetes Control and Complication Trial (DCCT) research results, the recently published Action to Control Cardiovascular Risk in Diabetes (ACCORD), Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE), and Veterans Affairs Diabetes Trial (VADT) research, as well as meta-analyses. Professor Jeong-Taek Woo reported on the manuscript written by the committee for the Korean Diabetes Association which dealt with the treatment of diabetes mellitus. Professors Kyung Soo Ko, Joong Yeol Park, Hyun Shik Son, Moon-Kyu Lee, Dong-Won Byun, and Yoon-Sok Chung participated in the discussion and collected information for the manuscript from all of the participants. The aim of the debate was to determine how to establish target goals for intensive glucose control and how to individualize those goals. The participants concluded that there was no need to modify the recommendation of maintaining an HbA1c under 6.5%, the current blood glucose treatment goal that is recommended by the Korean Diabetes Association. In addition, individual target goals for glucose control were recommended depending on the situation of each patient. We report on the consensus statement from the meeting.

Effects of perindopril and spirolactone on plasma aldosterone and left atrial remodeling in a canine model of atrial fibrillation / 中华心血管病杂志

<p><b>OBJECTIVE</b>To investigate the effects of perindopril and spirolactone on plasma aldosterone (Ald) and left atrial remodeling and function in a canine model of atrial fibrillation (AF).</p><p><b>METHODS</b>Adult dogs were randomly assigned to receive normal diet (group A), perindopril (group B, 1 mgxkg(-1)xd(-1)) and spironolactone (group C, 10 mgxkg(-1)xd(-1), n = 6 each) and rapid paced (500 beats/min) for 8 weeks. Plasma Ald levels as well as atrial dimension and function at baseline and at 4 and 8 weeks after pacing were measured by RIA and echocardiography, respectively. Incidence of maintained AF and AF duration were recorded when pacing was stopped after 8 weeks of pacing. Left and right atrial tissues were collected for measurements of tissue Ald levels and fibrosis.</p><p><b>RESULTS</b>Plasma Ald was similar among groups at baseline (P > 0.05) and significantly increased post 4 and 8 weeks pacing in group A (P < 0.05) while remained unchanged post pacing in group B and C (P > 0.05) compared to respective baseline level. Atrial Ald was significantly lower in group B and C compared that in group A post 8 weeks pacing (P < 0.05). Left atrial dimension, end-systolic and end-diastolic volume were significantly increased while left atrial ejection fraction (LAEF) was significantly reduced post pacing in group A (all P < 0.05 vs. baseline) and thses changes were significantly attenuated in group B and C (P < 0.05 vs. group A). Incidence of maintained AF and AF duration post pacing as well as interstitial collagen volume fraction were significantly lower in group B and C compared those in group A (P < 0.05).</p><p><b>CONCLUSION</b>Increased Ald might be an important pathogenesis for AF formation and progression, spironolactone and perindopril could attenuate atrial remodeling and improve atrial function by reducing plasma and tissue Ald levels in this model.</p>

Effect of carvedilol and perindopril on Ca(2+) pump activity and Ca(2+)-release channel density in myocardial sarcoplasmic reticulum in rats with chronic heart failure following myocardial infarction / 南方医科大学学报

<p><b>OBJECTIVE</b>To study the effects of carvedilol combined with perindopril on Ca(2+) pump activity and the density of Ca(2+)-release channel ryanodine receptor (RyR2) in the myocardial sarcoplasmic reticulum (SR) in rats with chronic heart failure caused by myocardial infarction.</p><p><b>METHODS</b>Rat models of chronic heart failure established by left coronary artery ligation were divided into different groups and treated with carvedilol (6 mg.kg(-1).d(-1)), perindopril (4 mg.kg(-1).d(-1)), terazosin (2 mg.kg(-1).d(-1)), or the combination of carvedilol (6 mg.kg(-1).d(-1)) and perindopril (4 mg.kg(-1).d(-1)) for 9 weeks. Another 12 rats with sham operation served as the sham-operated group. The hemodynamic parameters, activity of SR Ca(2+) pump, and RyR2 density were determined.</p><p><b>RESULTS</b>Compared with shame-operated group, the rats with chronic heart failure showed significantly increased left ventricular end-diastolic pressure (LVEDP) (P<0.01) and decreased +dP/dtmax, -dp/dtmax, activity of SR Ca(2+) pump and density of RyR2 (P<0.01). Both monotherapies with carvedilol and perindopril attenuated the increment of LVEDP, and significantly increased +dp/dtmax, -dp/dtmax, activity of SR Ca(2+) pump and density of RyR2 (P<0.01). Combined treatment even further enhanced the therapeutic effects, whereas terazosin produced no obvious effect. The activity of SR Ca(2+) pump was strongly correlated to +dp/dtmax and -dp/dtmax (r=0.596 and 0.684, respectively, P<0.01).</p><p><b>CONCLUSION</b>Prolonged treatment with beta-blocker carvedilol in combination with ACE inhibitor perindopril may improve the hemodynamic parameters, enhance Ca(2+) pump activity and increase the density of RyR2 of myocardial SR more effectively than either monotherapy in preventing and treating chronic heart failure following myocardial infarction.</p>

Expression of HIF-1alpha in 5/6-nephrectomized rat models of chronic kidney fibrosis / 中南大学学报(医学版)

OBJECTIVE@#To determine the expression and effect of hypoxia-inducible factor 1alpha (HIF-1alpha) in chronic kidney fibrosis, and to observe the effect of perindopril on its expression.@*METHODS@#The rat models of chronic kidney fibrosis were induced by 5/6 nephrectomy, and 11 successful 5/6-nephrectomized rats were randomly assigned to 2 groups: a surgery group (n=6) and a treatment group (perindopril, n=5). A control group was induced by sham operation. Five weeks later, Picro-Sirius red stained was applied to measure collagen in the kidney, and Western blot was used to test HIF-1alpha protein; The expression of HIF-1alpha and CTGF mRNA in the kidney was analyzed by real-time PCR.@*RESULTS@#Picro-Sirius red stained revealed significant accumulation of collagens in the surgery group than the control group; and lower accumulation of collagens in the treatment group than the surgery group. Western blot showed higher deposit HIF-1alpha in the surgery group than the control group (P<0.01) and lower deposit HIF-1alpha in the treatment group than the surgery group (P<0.01). Real time PCR showed higher expression of HIF-1alpha and CTGF mRNA in the surgery group than the control group (P<0.01)and lower expression of HIF-1alpha and CTGF mRNA in kidney of the treatment group compared with the surgery group (P<0.01). The expression of CTGF had positive correlation with HIF-1alpha (r=0.68, P<0.01).@*CONCLUSION@#The HIF-1alpha may induce kidney fibrosis through CTGF. Perindopril may decrease the expression of HIF-1alpha and CTGF to ameliorate kidney fibrosis.

Perindopril, amlodipine and telmisartan improve arterial stiffness in patients with hypertension / 中华心血管病杂志

<p><b>OBJECTIVE</b>To investigate the effect of perindopril, amlodipine and telmisartan on improving the artery stiffness in patients with hypertension.</p><p><b>METHODS</b>Patients with primary hypertension were randomly assigned to perindopril (4 mg/day), Amlodipine (5 mg/day) and telmisartan (80 mg/day) regimen for 3 months (n = 34 each). Brachial-ankle pulse wave velocity (baPWV) was measured by an automatic brachial ankle pulse wave velocity device before the treatment, one-month and three-month after the treatment.</p><p><b>RESULTS</b>(1) SBP, DBP and PP were significantly decreased in all three groups (P < 0.001). There were no significant changes in HR in all three groups (P > 0.05). (2) BaPWV was significantly decreased in all three groups. In the perindopril, Amlodipine, telmisartan group, baPWV was (1859 +/- 492) cm/s, (1780 +/- 335) cm/s, (1859 +/- 337) cm/s before the treatment; was (1757 +/- 508) cm/s, (1647 +/- 285) cm/s, (1632 +/- 261) cm/s one-month after the treatment; was (1702 +/- 538) cm/s, (1559 +/- 288) cm/s, (1566 +/- 326) cm/s three-month after the treatment. Compare the baPWV one-month after the treatment to before the treatment P < 0.001; Compare the baPWV three-month after the treatment to before the treatment P < 0.001; Compare the baPWV three-month to one-month after the treatment perindopril group and telmisartan group P < 0.01, amlodipine group P < 0.001. (3) The changes of baPWV in one or three months were significantly more in the telmisartan group than in the perindopril and amlodipine groups (1 months P < 0.01, 3 months P < 0.05). The change of baPWV was significantly greater in three months than in one montin in all three grops (P < 0.01).</p><p><b>CONCLUSION</b>Arterial stiffness of hypertensive patients was improved post Telmisartan, amlodipine and perindopril therapy in proportion to therapy duration. Telmisartan is superior to amlodipine and perindopril on improving arterial stiffness of hypertensive patients. Continuous anti-hypertensive treatment with telmisartan, amlodipine and perindopril will have a persistent improvement of the artery flexibility.</p>

Effects of Angiotensin-Converting Enzyme Inhibitor on Arterial Stiffness, Diastolic Function, and Exercise Performance in Patients with Hypertension

BACKGROUND: The aim of this study was to investigate the relations between arterial stiffness, diastolic function, and exercise performance and the effects of angiotensin-converting enzyme inhibitor(ACEI), perindopril, in these three areas in patients with hypertension(HT). METHODS: A total of 39 patients(60.9+/-4.9 years, 23 males) with a newly diagnosed or untreated HT, stage I, were enrolled. Arterial stiffness measured by pulse wave velocity, diastolic function measured by echocardiography, and exercise performance and hemodynamic parameters measured by a treadmill exercise test were compared before and after 6 months of medical treatment with an ACEI. RESULTS: The parameters for arterial stiffness, diastolic function, and exercise performance did not show significant correlations with each other at baseline. Systolic(from 147.6+/-6.5mmHg to 134.3+/-9.6mmHg, p<0.001) and diastolic blood pressures(from 87.7+/-7.5mmHg to 82.9+/-6.2mmHg, p<0.001) decreased significantly after 6 months of ACEI treatment. Except for duration of total exercise time, the parameters for arterial stiffness, diastolic function, and the hemodynamic response to exercise also improved significantly after 6 months of ACEI treatment. CONCLUSION: Though the parameters for arterial stiffness, diastolic function, and exercise performance were not asso- ciated with each other at baseline, they all improved significantly after 6 months of medical treatment with an ACEI in elderly patients with stage I HT. The results of this study suggest the possibility of additional benefits of ACEI beyond lowering blood pressure.

Effects of perindopril and enalapril on atherosclerosis development of apolipoprotein E knockout mice / 中华心血管病杂志

<p><b>OBJECTIVE</b>To compare the effects of perindopril and enalapril on the development of atherosclerotic lesions in ApoE knockout mice.</p><p><b>METHODS</b>ApoE knockout mice were treated with perindoprilor (1.5 mg.kg(-1).d(-1), n = 20), enalapril (7.5 mg.kg(-1).d(-1), n = 20) or saline (0.2 ml saline/d, n = 20) per gavage for 20 weeks. Blood pressure and lipids were measured at the study end. Aortic root atherosclerotic plaque was then quantified and the content of collagen and the size of lipid core in the plaque assessed. Cryostat sections were used to quantify the expressions of monocyte/macrophage-2 (MOMA-2), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and matrix metalloproteinases-9 (MMP-9) in the plaque by immunofluorescence method.</p><p><b>RESULTS</b>Blood pressure and lipid profiles were similar among different groups. Compared with control group, the plaque areas of perindopril group and enalapril group displayed significantly decrease (25.33% and 22.86%, respectively, both P < 0.01). However, no significant different were observed in the plaque size between the different ACE inhibitors groups. Perindopril group and enalapril group also significantly decreased the size of lipid core (52.98% and 38.98%, respectively, both P < 0.01) and the expression of MOMA-2 (88.38% and 52.16%, respectively, both P < 0.01), ICAM-1 (80.87% and 49.59%, respectively, both P < 0.01), VCAM-1 (77.56% and 56.44%, respectively, both P < 0.01) and MMP-9 (86.93% and 55.56%, respectively, both P < 0.01), and increased the plaque collagen content (298.36% and 168.14%, respectively, both P < 0.01) and the effects of perindopril was superior to those of enalapril (all P < 0.05).</p><p><b>CONCLUSIONS</b>ACE inhibitors significantly suppressed tissue inflammation and attenuated the development of atherosclerosis in ApoE knockout mice independent of their effects on the lipid and blood pressure. Perindopril is superior to enalapril in stabilizing the plaques and has similar effect on reducing the plaque size as that of enalapril.</p>

Perindopril and losartan attenuate bleomycin A5-induced pulmonary fibrosis in rats / 南方医科大学学报

<p><b>OBJECTIVE</b>To evaluate the effects of angiotensin-converting enzyme inhibitor (ACEI) and angiotensin II type 1 receptor (AT-1 receptor) blocker on the progression of rat pulmonary fibrosis induced by bleomycin A5.</p><p><b>METHODS</b>Twenty-four male Wistar rats were randomized into pulmonary fibrosis model, perindopril treatment, losartan treatment and control groups. In the former 3 groups, pulmonary fibrosis was induced via intratracheal injection of bleomycin A5 (5 mg/kg), after which the rats in the perindopril and losartan groups received intragastric administration of the corresponding agents at the daily dose of 2 mg/kg and 10 m/kg, respectively. The rats in the control group had intratracheal injection of normal saline only. In the 4th week, the histological changes of the lung tissues were examined microscopically with Masson staining. Hydroxyproline content in the lungs was measured, and the protein expressions of AT-1 receptor, TGF-beta1 and IkappaBalpha were examined using Western blotting. DNA binding activity of NF-kappaB was analyzed with electrophoretic gel mobility shift assay (EMSA), and zymography was used to assess the activity of matrix metalloproteinase-2 and 9 (MMP-2, 9).</p><p><b>RESULTS</b>Both perindopril and losartan treatment significantly reduced the pulmonary fibrosis score, content of hydroxyproline, protein expression of TGF-beta1, DNA binding activity of NF-kappaB and MMP-2, 9 activity, and increased cytoplasmic protein expression of IkappaBalpha. Perindopril treatment lowered the protein level of AT-1 receptor.</p><p><b>CONCLUSION</b>Perindopril and losartan may inhibit bleomycin A5-induced pulmonary fibrosis in rats by reducing the protein expression of TGF-beta1 and suppressing the DNA binding activity of NF-kappaB and MMP-2, 9 activity.</p>

Molecular mechanism of limbs' postischemic revascularization improved by perindopril in diabetic rats / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Currently, there are still divergent opinions about the mechanisms of the impaired neovascularization in diabetic subjects. Due to the remarkable therapeutic effect of angiotensin-converting enzyme inhibititors (ACEIs) on the reduction of blood pressure and the protection of target organs, the clinical application of this kind of drugs is very widespread. However, it is still not clear about the role and related molecular pathway of this kind of drugs in the limbs' postischemic revascularization. It is of major therapeutic importance to resolve these questions. This study aimed to investigate the reasons of the impaired angiogenesis in the hind limbs of rats with diabetic ischemia, the role and related molecular mechanisms of ACEI in postischemic revascularization.</p><p><b>METHODS</b>Hind limbs ischemia was induced in diabetic rats by right femoral artery excision. Diabetic rats were randomly allocated to one of the following treatments for 4 weeks: ACEI by perindopril; perindopril in combination with a nitric oxide synthase (NOS) inhibitor; perindopril in combination with bradykinin (BK)-B1 receptor (B1R) antagonist or saline. The differences of angiogenesis, the mRNA and protein expression of endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF) and basic fibroblast (bFGF), constitutive nitric oxide synthase (cNOS) activity and nitric oxide (NO) content were observed after treatment.</p><p><b>RESULTS</b>In non-ischemic hind limbs, no significant changes in capillary density, or the mRNA and protein expression of eNOS, VEGF and bFGF, or the NO content and the cNOS activity were observed among all groups. On the contrary, in ischemic hind limbs, the capillary density in diabetic rats decreased by 27% when compared with the control rats, so did the mRNA and protein expression of eNOS, VEGF and bFGF, or the NO content and the cNOS activity (P < 0.05). The capillary density was increased by 1.65-fold in the perindopril treatment group in reference to untreated diabetic rats. Moreover, administration of perindopril enhanced the mRNA expression of eNOS, VEGF, and bFGF by 1.45-, 1.44-, and 1.33-fold, increased the protein content of the above indices by 1.55-, 1.30- and 1.50-fold compared with the untreated diabetic rats respectively. Perindopril also increased NO content and cNOS activity to 1.33- and 1.38-fold of that in untreated diabetic rats. The combination of BK-B1R antagonist significantly decreased the above indices (P < 0.05). In contrast, the combination of NOS inhibitor decreased the expression of eNOS and bFGF, the NO content and the cNOS activity, while the expression of VEGF did not change.</p><p><b>CONCLUSIONS</b>Diabetes mellitus reduces the neovascularization, related growth factors expression and activity in the diabetic rat ischemic legs model. Treatment of perindopril improves postischemic revascularization. This effect is mediated, at least in part, by the BK-B1R-related pathway, and the activation of VEGF/eNOS/bFGF signals may be involved in the pro-angiogenic effect.</p>