Effect of edaravone in diabetes mellitus-induced nephropathy in rats

Edaravone, a synthetic-free radical scavenger, has been reported to reduce ischemia-reperfusion-induced renal injury by improving tubular cell function, and lowering serum creatinine and renal vascular resistance. The present study investigated the effect of edaravone in diabetes mellitus-induced nephropathy in rats. A single administration of streptozotocin (STZ, 55 mg/kg, i.p.) was employed to induce diabetes mellitus in rats. The STZ-administered diabetic rats were allowed for 10 weeks to develop nephropathy. Mean body weight, lipid alteration, renal functional and histopathology were analysed. Diabetic rats developed nephropathy as evidenced by a significant increase in serum creatinine and urea, and marked renal histopathological abnormalities like glomerulosclerosis and tubular cell degeneration. The kidney weight to body weight ratio was increased. Moreover, diabetic rats showed lipid alteration as evidenced by a signifi cant increase in serum triglycerides and decrease in serum high-density lipoproteins. Edaravone (10 mg/kg, i.p., last 4-weeks) treatment markedly prevented the development of nephropathy in diabetic rats by reducing serum creatinine and urea and preventing renal structural abnormalities. In addition, its treatment, without significantly altering the elevated glucose level in diabetic rats, prevented diabetes mellitus-induced lipid alteration by reducing serum triglycerides and increasing serum high-density lipoproteins. Interestingly, the renoprotective effect of edaravone was comparable to that of lisinopril (5 mg/kg, p.o, 4 weeks, standard drug). Edaravone prevented renal structural and functional abnormalities and lipid alteration associated with experimental diabetes mellitus. Edaravone has a potential to prevent nephropathy without showing an anti-diabetic action, implicating its direct renoprotection in diabetic rats.

Refractory intraoperative hypotension with elevated serum tryptase

Severe intraoperative hypotension has been reported in patients on angiotensin-converting enzyme inhibitors and angiotensin II receptor subtype 1 antagonists. We describe a patient on lisinopril who developed refractory intraoperative hypotension associated with increased serum tryptase level suggesting mast cell activation (allergic reaction). However, allergology workup ruled out an allergic etiology as well as mastocytosis, and hypotension recalcitrant to treatment was attributed to uninterrupted lisinopril therapy. Elevated serum tryptase was attributed to our patient's chronic renal insufficiency.

[Comparative study between captopril and lisinopril in their potential protective role in 5-fluorouracil-induced toxicity in experimental animals]

To compare between Captopril and Lisinopril in their potential protective role in 5-flurouracil- induced Cardiotoxicity, Hepatotoxicity and Nephrotoxicity in Experimental animals. The current study was conducted in the Department of Pharmacology -UST.24 adult male rabbits were divided to 4 groups. The first group was kept as a reference control group given normal saline i.p. Induction of toxicity was achieved by administration 5FU i.p to the remaining second, third and fourth groups. At the same time third and fourth group were treated by captopril [0.7 mg/kg i.p] and [0.1mg/kg i.p] respectively. All drugs [isotonic solution] were given to experimental animals for 14 days. Blood samples were collected before and after experiment to measure the biochemical parameters. The effects of captopril and lisinopril on cardiac, liver and kidney function enzymes after continuous administration of 5FU [10 mg/kg] i.p were measured.. Captopril showed significant reduction in cardiac enzymes from 1168.5 +/- 233.0 u/l, 416.4 +/- 26.7 u/l in 5FU to 727.83 +/- 131.4 u/l, 216.9 +/- 40.7 u/l for creatine kinase and lactic dehydrogenase respectively in captopril-treated group. In addition, lisinopril showed significant improvement in cardiac enzymes from 1168.5 +/- 233.0 u/l for creatine kinase, 416.4 +/- 26.7 u/l for lactic dehydrogenase in 5FU to 464.5 +/- 131.5 u/l, 108.7 +/- 8.84 u/l in lisinopril-treated group for 14 days. Lisinopril showed more significant in this respect. According to hepatoprotective effect both drugs showed insignificant improvement as compared with 5FU-group. On the other hand, captopril showed nephroprotective effect for kidney as it improved the renal function enzymes from 78.48 +/- 4.1 mg/dl of creatinine, 1.84 +/- 0.163 mg/dl of urea in 5FU group to 51.35 +/- 6.67mg/dl, 0.687 +/- 0.059 mg/dl of creatinine and urea respectively in captopril-treated group. Both drugs showed significant improvement in cardiac enzymes. Lisinopril was more effective in this respect. Both drugs showed insignificant hepatoprotective effect, while captopril showed significant nephroprotective effect. From these results, it was suggested that captopril and lisinopril could be used to prevent toxicity-induced by anticancer drugs

Effect of Eplerenone, a Selective Aldosterone Blocker, on the Development of Diabetic Nephropathy in Type 2 Diabetic Rats

BACKGROUND: Aldosterone antagonists are reported to have beneficial effects on diabetic nephropathy by effective blocking of the renin-angiotensin-aldosterone system. We investigated the renoprotective effect of the selective aldosterone receptor blocker eplerenone, the angiotensin converting enzyme inhibitor lisinopril, and combined eplerenone and lisinopril treatment in type 2 diabetic rats. METHODS: Animals were divided into six groups as follows: Otsuka Long-Evans Tokushima Fatty (OLETF) rat control, OLETF rats treated with a low dose of eplerenone (50 mg/kg/day), OLETF rats treated with a high dose of eplerenone (200 mg/kg/day), OLETF rats treated with lisinopril (10 mg/kg/day), OLETF rats treated with a combination of both drugs (eplerenone 200 mg/kg/day and lisinopril 10 mg/kg/day), and obese non-diabetic Long-Evans Tokushima Otsuka rats for 26 weeks. RESULTS: Urinary albumin excretion was significantly lower in the lisinopril group, but not in the eplerenone group. Urinary albumin excretion was decreased in the combination group than in the lisinopril group. Glomerulosclerosis and renal expression of type I and type IV collagen, plasminogen activator inhibitor-1, transforming growth factor-beta1, connective tissue growth factor, and fibronectin mRNA were markedly decreased in the lisinopril, eplerenone, and combination groups. CONCLUSION: Eplerenone and lisinopril combination showed additional benefits on type 2 diabetic nephropathy compared to monotherapy of each drug.

Terapia com inibidor da ECA com dosagens relativamente altas e risco de agravamento renal na insuficiência cardíaca crônica / ACE-inhibitor therapy at relatively high doses and risk of renal worsening in chronic heart failure

FUNDAMENTO: O efeito renoprotetor dos inibidores da ECA vem sendo questionado no caso de diminuição do volume circulante efetivo, como na insuficiência cardíaca crônica direita ou biventricular. Objetivo: Detectar os preditores clínicos de agravamento renal na população de pacientes com ICC, caracterizado por dois tipos de regime de dosagem de inibidores da ECA. MÉTODOS: De acordo com um desenho de coorte retrospectiva, seguimos dois grupos de pacientes com ICC - tanto direita quanto biventricular -, todos na classe III da NYHA, tratados com inibidores da ECA (enalapril ou lisinopril), e com fração de ejeção do ventrículo esquerdo (FEVE) < 50 por cento, por meio de distinção em sua dosagem de inibidor da ECA: média-baixa (< 10 mg por dia) ou dosagem "alta" (> 10 mg por dia) de enalapril ou lisinopril. A disfunção renal agravada (ARD) foi definida pelo aumento de Cr > 30 por cento com relação ao segmento basal. O modelo de risco proporcional de Cox foi utilizado para identificar os preditores da ARD entre as seguintes variáveis: os inibidores da ECA com "alta" dosagem, idade, FEVE basal, histórico de repetidas terapias intensivas com diuréticos de alça por via intravenosa (diurético intravenoso), diabete, Cr basal, histórico de hipertensão, pressão arterial sistólica < 100 mmHg. RESULTADOS: Cinquenta e sete pacientes foram recrutados, dos quais 15 foram tratados com inibidor da ECA com dosagem "alta". Durante um seguimento médio de 718 dias, a ARD ocorreu em 17 pacientes (29,8 por cento). Apenas o inibidor da ECA com "alta" dosagem (RR: 12,4681 IC: 2,1614 - 71,9239 p = 0,0050) e Cr basal (RR:1,2344 IC: 1,0414 - 1,4632 p = 0,0157) foi demonstrado ser preditor da ARD. Além disso, demonstrou-se que o inibidor da ECA com dosagens "altas" não previu ARD em ICC sem diurético intravenoso e ICC com diabete. CONCLUSÃO: Na ICC de classe III da NYHA, o inibidor da ECA com "altas" dosagens e um maior Cr basal foi preditor da ARD. A nefrotoxicidade relacionada com inibidores da ECA em "altas" dosagens foi aumentada com o diurético intravenoso, ao passo que, em pacientes com ICC com diabete, aquela não foi detectada.

BACKGROUND: Renoprotective effect of ACE-inhibitors has been questioned in case of decreased effective circulating volume, like in right or biventricular chronic heart failure. OBJECTIVE: To detect clinical predictors of renal worsening in CHF patient population characterized by two types of ACE-inhibitor dosing regimens. METHODS: According to a retrospective cohort design, we followed 2 groups of patients with CHF - whether right or biventricular -, all in III NYHA class treated with ACE-inhibitors (enalapril or lisinopril), and with left ventricular ejection fraction (LVEF) < 50 percent, by distinguishing them by ACE-inhibitor dosing: average-low (<10 mg per day) or "high" dose (>10 mg per day) of enalapril or lisinopril. Worsened renal failure (ARD) was defined by Cr increase >30 percent from baseline. Cox proportional hazards model was used to identify the predictors of ARD among the following variables: ACE-inhibitors "high" dose, age, basal LVEF, history of repeated intensive intravenous loop diuretic therapies (IV diur), diabetes, basal Cr, history of hypertension, systolic blood pressure < 100 mm Hg. RESULTS: 57 patients were recruited, of whom 15 were treated with ACE-inhibitor "high" dose. During a mean follow-up of 718 days, ARD occurred in 17 (29.8 percent) patients. Only ACE-inhibitor "high" dose (HR: 12.4681 C.I.: 2.1614-71.9239 p=0.0050) and basal Cr (HR: 1.2344 C.I.: 1.0414-1.4632 p=0.0157) were shown to predict ARD. Moreover, ACE-inhibitor "high" doses were shown to fail to predict ARD in both CHF without IV diur and CHF with diabetes. CONCLUSION: In III NYHA class CHF, ACE-inhibitor "high" doses and a higher basal Cr predicted ARD. Nephrotoxicity related to ACE-inhibitor "high" doses was increased by IV diur, whereas it was not detected in CHF patients with diabetes.

Pharmacokinetics of the combined preparation of lisinopril and hydrochlorothiazide on Chinese healthy volunteers / 药学学报

The aim of the present study, performed on two different groups of volunteers, is to characterize the pharmacokinetics of lisinopril/hydrochlorothiazide combined tablet. After administration of high, medium and low doses of lisinopril/hydrochlorothiazide combined tablets, AUC and C(max) of two compounds both increase significantly with increase of dose. Neither normalized AUC/Dose nor C(max)/Dose has significant difference between every two tested dose groups. The similar results can be observed as for the parameters of t(max). Lisinopril and hydrochlorothiazide are both eliminated with linear characteristics. After repeated administration of lisinopril/hydrochlorothiazide combined tablets, AUC, C(max) and C(min) of lisinopril in the steady state increase. AUC and C(min) increase significantly. As for hydrochlorothiazide, AUC, C(max), C(min), and t(max) also increase in steady state. AUC and C(min) increase significantly. Administered with the test medication, lisinopril has an fluctuation index (FI) value of 2.29 and reaches a relative steady concentration. But hydrochlorothiazide has an FI value of 4.09 with relatively large fluctuating concentrations.

The effect of anti-hypertensive drugs on the obstructive pancreatitis in rats / Efeitos de fármacos anti-hipertensivos sobre pancreatite obstrutiva em ratos

PURPOSE: To investigate the effect of ACE inhibitor, lisinopril and AT1 blocker, losartan, on the obstructive pancreatitis in rat. METHODS: Acute pancreatitis in rats (n=21) was induced for a common hepatic duct were ligated proximal to its entry into the pancreas and the common bile - pancreatic duct were also ligated near its junction with the duodenum, under ether anesthesia, after which the abdomen were closed. The animals was divided in tree groups, being two treated and control group. The animals was treated with Losartan and Lisinopril at the dose of 10µg/Kg body weight per day, i.p., in a proportional volume, for five days, before and after treatement. RESULTS: The inflammation, collagen deposition in the pancreas of treated animals were smaller, suggesting that the use of antihypertensive agents interfered positively in the depletion of the injury of the pancreas. Scythe showed a correlation between activity of pancreatic stellate cells (PSCs) lower in treated animals when compared to control. CONCLUSION: The pancreatic stellate cells strength are involved in collagen production during acute pancreatitis and why antihypertensive drugs such as lisinopril and losartan may possibly have beneficial effects in reducing pancreatic fibrosis in models of experimental obstructive pancreatitis.

OBJETIVO: Investigar o efeito de um inibidor da ECA, lisinopril e bloqueador AT1, losartan, a pancreatite obstrutiva em ratos. MÉTODOS: Pancreatite aguda em ratos (n = 21) foi induzida por um ducto hepático comum foram ligados proximal à sua entrada no pâncreas e da bílis comum - ducto pancreático também foram ligados perto de sua junção com o duodeno, sob anestesia com éter, após o que abdome foram fechadas. Os animais foram divididos em três grupos, sendo dois tratados eo grupo controle. Os animais foram tratados com lisinopril e losartan na dose de 10µg/Kg de peso corporal por dia, IP, em um volume proporcional, por cinco dias, antes e depois do tratamento com. RESULTADOS: A inflamação, deposição de colágeno no pâncreas de animais tratados foram menores, sugerindo que o uso de agentes anti-hipertensivos interferiram positivamente na diminuição da lesão do pâncreas. Este estudo mostrou uma correlação entre a atividade das células pancreáticas estreladas (CSP) menor nos animais tratados quando comparados ao control. CONCLUSÃO: A força das células pancreáticas estreladas está envolvida na produção de colágeno durante a pancreatite aguda e por medicamentos anti-hipertensivos, tais como lisinopril e losartan pode eventualmente ter efeitos benéficos na redução da fibrose do pâncreas em modelos experimentais de pancreatite obstrutiva.

Ação do lisinopril e do losartan na função endotelial após infarto agudo do miocárdio. Estudo experimental em ratos / Action of lisinopril and losartan in endothelial function after acute myocardialinfarction. Experimental study in rats.

JUSTIFICATIVA E OBJETIVOS: O presente estudo teve como objetivo estudar a influência do lisinopril e do losartan na função endotelial em ratos com infarto experimental do miocárdio. MÉTODO: Ratos Wistar machos, peso entre 350 e 400 g, divididos em quatro grupos (n igual 10): G1 igual ratos controle sem infarto, G2 igual ratos com infarto, G3 igual ratos com infarto e tratados com lisinopril (20 mg/kg/dia) e G4 igual ratos com infarto e tratados com losartan (30 mg/kg/dia). Os fármacos foram administrados via gavagem dois dias antes do infarto e continuado por mais sete dias. Os ratos foram anestesiados com éter para a ligadura da coronária descendente anterior. Após nove dias os animais foram anestesiados, o coração excisado e verificado a extensão do infarto. Utilizou-se para este fim a coloração pelo método do cloreto de trifeniltetrazólio a 1%, se considerando infarto grande quando excedia 40% da área do ventrículo esquerdo. A função endotelial foi verificada através de curva de concen­tração efeito com acetilcolina em segmento proximal da aorta torácica. Foram utilizados os testes estatísticos de ANOVA e de Duncan, sendo considerado significativo o valor de p menor que 0,05. RESULTADOS: Os resultados obtidos para a função en­dotelial para o relaxamento máximo foram: G 1 igual 78,24% mais ou menos 3,57%; G2 igual 14,04% mais ou menos 5,20%, G3 igual 48,94% mais ou menos 9,29% e G4 igual 26,98% mais ou menos 7,80%. Houve diferença estatístíca significatíva para entre os G3 e G4. CONCLUSÃO: Ocorreu disfunção endotelial em ratos na fase recente do infarto do miocárdio e o tratamento com lisinopril e losartan melhoraram esta disfunção endotelial.

A case of renal transplantation.

A 12-year-old boy was admitted in paediatric nephrology unit of Bangabandhu Sheikh Mujib Medical University (BSMMU) with massive proteinuria, hypertension, respiratory distress and anaemia and diagnosed as nephrotic syndrome. Percutaneous needle biopsy was consistent with diffuse endocapillary proliferative glomerulonephritis and initially managed conservatively with injection methyl prednisolone, cyclophosphamide, lisinopril etc. without any improvement. Living-related renal transplantation was done successfully from paternal uncle. Two episodes of acute rejection occurred, one immediately after transplantation and another after one month. These were managed with IV methyl prednisolone for 3 days. At present, he is on oral prednisolone, cyclosporine, azathioprine and antihypertensives with normal haemoglobin and stable serum creatinine level (pre-transplant level 12.5mg/dl to post-transplant level 1.5mg/dl). He has been maintaining his normal life including schooling for last few months. It is concluded that a patient with uncommon presentation of nephrotic syndrome should be confirmed by renal biopsy and renal transplantation may be considered if conservative measures fail.

Antidepressant activity of fosinopril, ramipril and losartan, but not of lisinopril in depressive paradigms of albino rats and mice.

Fosinopril, ramipril and losartan significantly decreased the duration (sec) of immobility in forced swim test and were comparable to amitriptyline. The duration of immobility were significantly decreased in fosinopril, ramipril and losartan in the tail suspension test and were comparable to amitriptyline. Only losartan significantly increased the rearing number of entries, time spent (sec) in open arm and in light area in comparison to control animals. Fosinopril and ramipril and not lisinopril showed significant antidepressant activity while losartan showed a significant antidepressant and anxiolytic activity. Present findings suggest that these drugs could be better antihypertensives in hypertensive patients with comorbidity like depression or anxiety.

comparative study of the effect of peroxisome proliferator activated receptor gamma agonist and angiotensin converting enzyme inhibitor on experimental pancreatitis in rats

There is accumulating evidence that peroxisome proliferators-activated receptor gamma [PPARgamma] plays important roles in the processes of fat metabolism, adipocyte differentiation, tumorigenesis, inflammation, and a variety of immune processes. Thiazolidinediones [TZDs], including rosiglitazone, are high-affinity ligands for [PPAR-gamma] and are used as insulin-sensitizing drugs. They inhibit chernokines [interleukin-8] in epithelial cells, leading to the suggestion of their use in inflammation. Angiotensin-converting enzyme [ACE] inhibitors are commonly prescribed to reduce the risk of myocardial infarction and cardiovascular death. They also modulate proinflammatory signals and reduce macrophage accumulation. Thus, they may have beneficial action in various inflammatory conditions. The present study aimed to investigate the possible anti-inflammatory effects of [PPAR] gamma agonist [rosiglitazone] and ACE inhibitor [lisinopril] in cerulein-induced chronic pancreatitis [CP] in rats. Also to compare between their actions, separately or in combination, in CP. Fifty male albino rats weighing from 150-200 gm were included in this study. Rats were divided into two main groups. Group 1, [10 rats] served as a control group, they were received 1 ml physiological saline [0.9%], by intraperitoneal [i.p.] injections six hourly, three times a week for three weeks. Group II: cerulein-induced CP group [40 rats] injected with cerulein i.p. in a dose of 50 microg/kg.b.wt. six hourly, three times a week for three weeks. Rats were further subdivided into A, B, C, and D, each often rats. Group- A received 1ml of 2% gum acacia daily orally for two weeks starting from the third week of cerulein administration. Groups B and C treated with rosiglitazone in a dose of 3 mg/kg.b.wt. or lisinopril in a dose of 2.5 mg/kg.b.wt orally daily for the same previous duration. Group-D, treated with both drugs for the same previous doses and duration. I.p. injection of cerulein produced significant increases in serum levels of amylase, tumor necrosis factor-alpha [TNF-alpha] and transforming growth factor-beta 1 [TGF- beta1] with elevations of pancreatic tissue content of hydroxyproline [HPO] and myeloperoxidase [MPO] activity. Rosiglitazone and lisinopril produced improvement of CP manifested by the significant decreases in the previous measured parameters, but rosiglitazone, provided a better effect. Combined administration of rosiglitazone and lisinopril, produced marked and superior ant-inflammatory and antifibrotic actions. I.p. injection of cerulein is a reliable method for induction of CP resembles the human CP. RAS proved to be incriminated in the pathogenesis of CP as evidenced by the effective therapeutic effect of lisinopril in cerulein-induced CP. Rosiglitazone, provided a better effect than lisinopril, reflecting the important role of PPARgamma in CP. The combination of both drugs proved to be superior in alleviated chronic pancreatitis which may be due to the synergistic anti-inflammatory, anti-oxidant and antifibrotic effects of these drugs

Efecto de la n-acetilcisteína, valsartan y lisinopril en la prevención de la disfunción renal precoz secundaria a neumoperitoneo: modelo en ratas / Effect of n-acetylcysteine, valsartan and lisinopril in preventing renal insufficiency secondary to pneumoperitoneum in a rat model

Introducción: El trasplante renal es el tratamiento de elección para los pacientes en insuficiencia renal terminal. A pesar que la nefrectomía clásica del donante vivo ha resultado ser un procedimiento seguro y bien tolerado, existen factores que desincentivan este acto de donación. La nefrectomía laparoscópica del donante vivo ha dado una respuesta a este último punto. Sin embargo, varios investigadores han comunicado mayor disfunción renal precoz en riñones procurados laparoscópicamente en comparación con los procurados en forma clásica abierta. Existe información que la Nacetilcisteina y Valsartán tendrían un efecto protector frente al neumoperitoneo. Con respecto al Lisinopril (inhibidor ECA) existen datos disímiles. El objetivo de este trabajo es evaluar la utilidad dela N-acetilcisteína, Valsartán y Lisinopril en la prevención de la disfunción renal precoz de riñones sometidos a neumoperitoneo en un modelo en ratas. Material y métodos: Se utilizaron 40 ratas Sprague Dawley, macho, de 250 a 300 g, separadas en 4 grupos: Grupo 1: 10 ratas sometidas a hidratación subcutánea con solución salina (control), Grupo 2: 10 ratas sometidas a hidratación subcutánea con solución salina más N-acetilcisteina, Grupo 3: 10ratas sometidas a hidratación subcutánea con solución salina más Valsartán, y Grupo 4: 10 ratas sometidas a hidratación subcutánea con solución salina más Lisinopril. Las ratas fueron anestesiadas y colocadas en neumoperitoneo a 12 mmHg por 90 minutos. Luego las ratas se colocaron en jaula metabólica donde se midió diuresis, presión arterial, función renal, microalbuminuria y enzimas tubulares. Las ratas fueron sacrificadas al séptimo día realizándose estudio histológico. En el análisis estadístico se utilizaron modelos lineales generalizados, análisis de la varianza (Anova) y test exacto de Fisher y Chi-cuadrado...

Introduction: Renal transplant it the treatment of choice for patients with terminal renal insufficiency. Classic open live donor nephrectomy is a safe and well tolerated procedure, however there some factors that may inhibit patients from donating. Laparoscopic live donor nephrectomy has gained wide acceptance, nevertheless several authors have reported early renal insufficiency in these patients compared to those harvested through the classic approach. Apparently n-acetylcysteine and valsartan would have a protective effect against pneumoperitoneum, however there is contradicting data for Lisinopril. We evaluate n-acetylcysteine, valsartan and lisinopril for prevention of early renal insufficiencyin kidneys undergoing pneumoperitoneum in a rat model. Material and methods: A total of 40 male rats (Sprague Dawley) of 250 and 300 grams were divided in4 groups. Group 1 (control): 10 rats with subcutaneous hydration with saline. Group 2: 10 rats with subcutaneous hydration with saline and n-acetylcysteine. Group 3: 10 rats with subcutaneous hydration with saline and Valsartan and Group 4: 10 rats with subcutaneous hydration with saline and Valsartan. All rats underwent general anesthesia with pneumoperitoneum at 12 mmHg for 90 minutes. Rats were placed in a metabolic cage where urine output, blood pressure, renal function, microalbuminuria and tubular enzymes were measured. At postoperative day seven, all animals were put to sleep and histological analysis was performed. Statistics was done using lineal generalized models, Anova, Fisher and Chi-square models were also used. Results: Pneumoperitoneum did not produce early renal insufficiency. Rats with lisinopril presented a decrease in creatinine clearance (0,92 ml/min) p=0,056; higher microalbuminuria (27073,9 mg/dl/creatininuria) p < 0,001 and more histological lesions p=0,017. Urine output, blood pressure, tubular...

Characterization of impurities in the bulk drug lisinopril by liquid chromatography/ion trap spectrometry / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Two trace impurities in the bulk drug lisinopril were detected by means of high-performance liquid chromatography coupled with mass spectrometry (HPLC/MS) with a simple and sensitive method suitable for HPLC/MSn analysis. The fragmentation behavior of lisinopril and the impurities was investigated, and two unknown impurities were elucidated as 2-(6-amino-1-(1-carboxyethylamino)-1-oxohexan-2-ylamino)-4-phenylbutanoic acid and 6-amino-2-(1-carboxy-3-phenylpro-pylamino)-hexanoic acid on the basis of the multi-stage mass spectrometry and exact mass evidence. The proposed structures of the two unknown impurities were further confirmed by nuclear magnetic resonance (NMR) experiments after preparative isolation.

Characterization of a novel impurity in bulk drug of lisinopril by multidimensional NMR technique / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

During the routine impurity profile of lisinopril bulk drug by HPLC (high-performance liquid chromatography), a potential impurity was detected. Using multidimensional NMR (nuclear magnetic resonance) technique, the trace-level impurity was unambiguously identified to be 2-(-2-oxo-azocan-3-ylamino)-4-phenyl-butyric acid after isolation from lisinopril bulk drug by semi-preparative HPLC. Formation of the impurity was also discussed. To our knowledge, this is a novel impurity and not reported elsewhere.

Left Ventricle Myocardium Volume Densities in Spontaneously Hypertensive Rats (SHR) Following Combination of Exercise and ACE Inhibitor Treatment: A Stereological Study / Densidad de Volumen del Miocardio del Ventrículo Izquierdo en Ratas Espontáneamente Hipertensas (REH) Posterior a la Combinación de Ejercicios y Tratamiento Inhibidor de la ACE: Estudio Estereológico

This study was designed to test the possible effects of a combination of physical and pharmacological therapy intervention on myocardial structure of the left ventricle in spontaneously hypertensive rats (SHR). Twelve weeks old spontaneously hypertensive rats (n = 40) were divided into four groups of sedentary, (Sed) as controls, exercise only (Exer), lisinopril only 20mg/kg/day (Lis), and exercise + lisinopril (LisExer). Exercise training was performed on a treadmill (5m/min.) for 60 minutes/day, 5 days/week for 10 weeks. At the end of 10 weeks, all the rats were terminally anaesthetised, the heart was arrested in diastole by intravenous procaine and whole animal perfusion fixation through the abdominal aorta was carried out using Karnovsky's fixative (pH 7.24). The heart was removed and left ventricle plus the interventricular septum was serially sectioned at a thickness of 3 mm. One piece was randomly chosen, and embedded in JB4 resin. Six sections were obtained from each block, stained with toluidine blue:acid fucin. Measurement of volume fraction (Vf), of myocardium, capillaries and interstitium were carried out using a stereology software (Histometrix MIL6 Kinetic imaging Ltd.). Mean Vf of capillaries in Sed group was 0.114 ± 0.01 (SEM). This was significantly increased in LisExer group. The Vf of muscle in Sed group was 0.795 ± 0.02 (SEM). This was significantly decreased in Lis but unchanged in Exer group. Capillaries Vf was significantly higher in LisExer as compared to Lis or Exer groups (p<0.05). Muscle Vf was not different betweenLisExer and Lis groups. The outcome of these changes could well be a better enhancement of cardiac performance in hypertension by combined exercise and ACE inhibitor treatment than either of the interventions alone.

Este estudio fue diseñado para probar los posibles efectos de una combinación de ejercicios y una intervención de terapia farmacológica en las estructuras del miocardio del ventrículo izquierdo, en ratas espontaneamente hipertensivas (SHR). Ratas de 20 semanas espontáneamente hipertensas (n = 40) fueron divididas en cuatro grupos: sedentarias (Sed) y controles, solamente con ejercicio (Ejer), solamente con lisinopril con 20mg/kg/día (Lis), y ejercicios + lisinopril (LisEjer). Los ejercicios fueron ejecutados en una máquina de entrenamiento (5m/min.) por 60 minutos/día, 5 días/semana por 10 semanas. Al término de las 10 semanas, las ratas fueron sacrificadas bajo anestesia, el corazón fue detenido en diástole usando procaina intravenosa. Los animales fueron perfundidos a través de la parte abdominal de la aorta, usando solución de Karnovsky (pH 7.24). El corazón fue removido y tanto al ventrículo izquierdo como al septo interventricular se les realizaron cortes seriados de 3 µm. Una pieza fue seleccionados al azar, y sumergida en resina JB4. Fueron obtenidas 6 secciones de cada bloque y luego teñidas con azul de toluidina:fucsina ácida. Las mediciones de fracción volumétrica (Vf) del miocardio, capilares, e intersticio fueron obtenidas usando un software de estereología (Histometrix MIL6 Kinetic imaging Ltd.). El promedio Vf de capilares en el grupo Sed, fue 0.114 ± 0.01 (SEM). Éste fue significativamente mayor en el grupo LisExer. El Vf de músculo en Sed fue 0.795 ± 0.02 (SEM). Éste fue significativamente menor en Lis pero no varió en el grupo Ejer. Vf capilares fue significativamente alto en LisExjr, si es comparado con los grupos Lis o Ejer (p<0.05). En Vf músculo no hubo diferencias entre los grupos LisEjer y Lis. El resultado de estos cambios pudo deberse a un mejor funcionamiento cardiaco en ratas hipertensa,s producto de ejercicios combinados y tratamiento con inhibidor ACE, que en aquellos en que se efectó un solo procedimiento.

O bloqueio do sistema renina-angiotensina atenua a remodelação cardíaca de ratos submetidos a estenose aórtica / Blockade of renin-angiotensin system attenuates cardiac remodeling in rats undergoing aortic stenosis

OBJETIVO: Avaliar o papel do bloqueador dos receptores AT1 e do inibidor da enzima conversora da angiotensina na remodelação cardíaca induzida por estenose aórtica em ratos. MÉTODOS: Ratos Wistar foram divididos em 4 grupos: controle (C, n=13), estenose aórtica (EAo, n=11), EAo com lisinopril, 20 mg/kg/dia (LIS, n=11) e EAo com losartan, 40 mg/kg/dia (LOS, n=9). Os tratamentos foram iniciados 3 dias antes da cirurgia. Após 6 semanas, os animais foram submetidos ao estudo ecocardiográfico, quantificação da concentração de hidroxiprolina e da área seccional (CSA) miocitária do ventrículo esquerdo (VE). RESULTADOS: A EAo induziu aumento da espessura da parede do VE. Os animais LIS e LOS não apresentaram diferença em relação aos animais controles. Os ratos EAo e LIS apresentaram maiores diâmetros do átrio esquerdo que os ratos controles, enquanto nos animais LOS não houve diferença. Os animais com EAo apresentaram maiores valores da porcentagem de encurtamento que os controle. Esse fato não foi modificado com LIS ou LOS. A CSA dos animais do grupo EAo foi maior que a dos controle. Entretanto, o tratamento com LOS e com LIS atenuou o aumento da área induzida pela EAo. A EAo resultou em aumento na concentração de HOP, enquanto o grupo LOS não apresentou diferença em relação ao grupo controle. CONCLUSÃO: O bloqueio do sistema renina-angiotensina, com bloqueador AT1 e com IECA, pode atenuar o desenvolvimento de hipertrofia cardíaca, porém só o bloqueio dos receptores AT1 atenua a fibrose intersticial do VE.

Efeitos da inibição prolongada da enzima de conversão da angiotensina sobre as características morfológicas e funcionais da hipertrofia ventricular esquerda em ratos com sobrecarga pressórica persistente / Effects of the prolonged inhibition of the angiotensin-converting enzyme on the morphological and functional characteristics of left ventricular hypertrophy in rats with persistent pressure overload

OBJETIVO: Avaliar os efeitos do lisinopril (L) sobre as taxas de mortes (M), insuficiência cardíaca (ICC), características da remodelação miocárdica, geométrica e funcional do ventrículo esquerdo (VE), em ratos com estenose aórtica supravalvar (EAS). MÉTODOS: Ratos foram submetidos a EAS ou cirurgia simulada (GC:n=10). Randomizados após 6 semanas para receber L (GL:n=30) ou nenhum tratamento (GE:n=73) sendo avaliados 6s e 21s por estudos ecocardiográfico, hemodinâmico e morfológico concomitantes. RESULTADOS: As taxas de M (GE: 53,9 por cento vs GL: 16,7 por cento e ICC GE: 44,8 por cento vs GL: 20 por cento p<0,05). No final do experimento, os valores da pressão sistólica do VE dos grupos GE e GL foram equivalentes e significantemente mais elevados do que no grupo GC; (p<0,05) não diferindo dos observados 6 semanas após os procedimentos cirúrgicos. Os valores da pressão diastólica do VE no grupo GE foram maiores do que os do grupo GL (p<0,05) sendo ambos maiores do que os do grupo GC (4 ± 2 mmHg, p<0,05). O mesmo comportamento foi observado com as variáveis: razão E/A; índice de massa, área seccional dos miócitos e conteúdo de hidroxiprolina do VE. A porcentagem de encurtamento do VE foi semelhante nos grupos GC e GL (p>0,05) sendo ambos maiores que os verificados no grupo GE. Comportamento semelhante foram obtidos com os valores da primeira derivada positiva e negativa da pressão do VE. CONCLUSAO: Em ratos com EAS o L reduziu as taxas de M e ICC e exerceu efeitos benéficos sobre a remodelação e a função do VE.

Remodelação miocárdica após infarto agudo do miocárdio experimental em ratos: efeito do bloqueio do sistema renina angiotensina aldosterona / Myocardial remodeling after experimental acute myocardial infarction in rats: effect of renin-angiotensin-aldosterone system blockade

OBJETIVO: Verificar a ação do lisinopril e do losartan sobre a remodelação miocárdica no infarto experimental em ratos. MÉTODOS: Ratos machos Wistar foram submetidos a infarto e tratados com lisinopril 20 mg/kg/dia (LIS, n=13) ou losartan 20 mg/kg/dia (LOS, n=11), ou mantidos sem tratamento (NT, n=11), por três meses e os resultados comparados com grupo controle (CONT, n=11) de ratos sem infarto. Após a eutanásia, o ventrículo esquerdo foi separado e pesado. Foram medidas a área seccional dos miócitos (AC), fração de colágeno intersticial (CVF) e a hidroxiprolina (HOP) miocárdica. As variáveis foram comparadas pela ANOVA de uma via, para nível de significância de p<0,05. RESULTADOS: O infarto agudo promoveu a hipertrofia do ventrículo esquerdo e os tratamentos com lisinopril e losartam preveniram a hipertrofia quantificada pelo peso do ventrículo esquerdo (LOS=1,06± 0,12g, LIS=0,97±0,18g, NT=1,26±0,17g, CONT=1,02± 0,09g; p<0,05), pelo peso de ventrículo esquerdo corrigido pelo peso corporal VE/PC (LOS=2,37±0,21mg/g, LIS=2,41± 0,38mg/g,NT=2,82±0,37mg/g, CONT=2,27± 0,15mg/g) e pela medida da AC do ventrículo esquerdo (LOS=210±39µ², LIS=217±35µ², NT=256±35µ², CONT= 158±06 µ²; p<0,05). O CVF foi significantemente maior no ventrículo esquerdo do grupo infartado e houve prevenção do aumento com os tratamentos (LOS=1,16±0,4 por cento, LIS=1,27± 0,5 por cento, NT=1,8± 0,4 por cento, CONT=0,7±0,5 por cento). A HOP foi maior no grupo infartado (NT=6,91±2,98mg/g vs. CONT=2,81±1,21mg/g) e não alterou com o tratamento. CONCLUSÃO: A remodelação miocárdica pós-infarto é caracterizada por aumento da massa ventricular remanescente e aumento de colágeno intersticial. O bloqueador da enzima conversora da angiotensina e o antagonista seletivo AT1 da angiotensina II previnem a hipertrofia do miócito e a fibrose intersticial.