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.

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.

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.

Effect of angiotensin-converting enzyme inhibitors, captopril and lisinopril, on collagen synthesis by cultured rat liver cells

Several studies have documented the role of angiotensin-converting enzyme inhibitors [ACEI] as antifibrogenic and antiproliferative in different tissues in vivo and in vitro but unfortunately non of them has investigated this effect on collagen synthesis by individual liver cells. In this study we focused on the in vitro effect of two ACEI with different pharmacologic properties, captopril and lisinopril, on the synthesis of types I and III collagens by individual liver cells, since these types of collagens are the most abundant ECM molecules both in normal and fibrotic liver. Rat liver cells were isolated, separated according to cell types through density gradient centrifugation in percoll then cultured as separate clones for 24 hours. Types I and III collagens secretion was measured by gel electrophoresis [SDS-PAGE] and computer analysis of their alpha chains after purification from cell culture media. Both captopril and lisinopril significantly reduced types I and III collagens by cultured hepatocytes [HC], liver endothelial cells [EC], and hepatic stellate cells [HSC] with more prominent action for captopril than lisinopril. The present study document the inhibitory effect of ACEI on types I and III collagen synthesis by liver cell sub-population in vitro by a mechanism independent on the systemic angiotensin-converting enzyme inhibition and possibly through a mechanism involving a local renin-angiotensin system or interference with intracellular events involved in collagen synthesis

Effect of antihypertensive agents on stellate cells during liver regeneration in rats

BACKGROUND: Although most studies have focused on the hepatocytes, all the hepatic cells participate in the regenerative process, among them the stellate cells. The stellate cells are mesenchymal cells involved in local neurotransmission and paracrine regulation of several liver functions. Acute hepatic tissue loss promotes the proliferation and activation of stellate cells from a quiescent state to myofibroblast-like cells. AIM: Investigate the effects of antihypertensive agents on the stellate cell population during the liver regenerative phenomenon in rats. METHODS: Adult male Wistar rats received lisinopril, losartan, bradykinin, or saline solution in a proportional volume, intraperitoneally, before and after 70 percent partial hepatectomy. Animals from the experimental and saline groups were sacrificed at 36 hours after partial hepatectomy. The alpha-smooth muscle actin labelled stellate cells population was counted in the periportal and pericentral zones of the liver specimen. RESULTS: The labelled stellate cells were more numerous in the control group both in the periportal and pericentral zones at 36 hours after partial hepatectomy than at the other times. The population of stellate cells was significantly lower in the losartan group and higher in the bradykinin and lisinopril groups than in the control group. CONCLUSIONS: These results suggest that losartan can inhibit and bradykinin and lisinopril can stimulate the stellate cell population during liver regeneration in rats. These cells synthesize several substances to stimulate liver regeneration.

Role of liquid membrane phenomenon in biological actions of ACE inhibitors, captopril and lisinopril.

The liquid membrane phenomenon in angiotensin converting enzyme (ACE) inhibitors namely, captopril and lisinopril has been studied. Hydraulic permeability data have been obtained to demonstrate the existence of the liquid membrane in series with a supporting membrane generated by the ACE inhibitors. Data on the transport of the relevant permeants in presence of the liquid membrane formed by ACE inhibitors indicate that liquid membrane phenomenon is likely to play a significant role in the action of ACE inhibitors.

Angiotensin-converting enzyme inhibition by lisinopril enhances liver regeneration in rats

Bradykinin has been reported to act as a growth factor for fibroblasts, mesangial cells and keratinocytes. Recently, we reported that bradykinin augments liver regeneration after partial hepatectomy in rats. Angiotensin-converting enzyme (ACE) is also a powerful bradykinin-degrading enzyme. We have investigated the effect of ACE inhibition by lisinopril on liver regeneration after partial hepatectomy. Adult male Wistar rats underwent 70 percent partial hepatectomy (PH). The animals received lisinopril at a dose of 1 mg kg body weight-1 day-1, or saline solution, intraperitoneally, for 5 days before hepatectomy, and daily after surgery. Four to six animals from the lisinopril and saline groups were sacrificed at 12, 24, 36, 48, 72, and 120 h after PH. Liver regeneration was evaluated by immunohistochemical staining for proliferating cell nuclear antigen using the PC-10 monoclonal antibody. The value for the lisinopril-treated group was three-fold above the corresponding control at 12 h after PH (P<0.001), remaining elevated at approximately two-fold above control values at 24, 36, 48 (P<0.001), and at 72 h (P<0.01) after PH, but values did not reach statistical difference at 120 h after PH. Plasma ACE activity measured by radioenzymatic assay was significantly higher in the saline group than in the lisinopril-treated group (P<0.001), with 81 percent ACE inhibition. The present study shows that plasma ACE inhibition enhances liver regeneration after PH in rats. Since it was reported that bradykinin also augments liver regeneration after PH, this may explain the liver growth stimulating effect of ACE inhibitors

Efeito do lisinopril na isquemia experimental em ratos. Influência do tamanho do infarto / Effects of lisinopril on experimental ischemia in rats. Influence of infarct size

OBJECTIVE - Angiotensin-converting enzyme inhibitors (ACEIs) have gained importance in preventing or attenuating the process of ventricular remodeling after myocardial infarction. The significance of infarct size in regard to the response to ACEIs, however, is controversial. This study aimed to analyze the effects of lisinopril on mortality rate, cardiac function, degree of cardiac hypertrophy and fibrosis in rats with different in. There was no statistical difference between the groups with small and large infarcts in regard to myocardial concentration of hydroxyproline. In small infarcts, the treatment attenuated the heart dysfunction characterized by lower levels of blood pressure and lower values of the first derivative of pressure and of the negative derivative of pressure. The degree of hypertrophy was also attenuated in small infarcts. In regard to large infarcts, no differences between the groups were observed. CONCLUSION - Treatment with the ACEIs had no effect on mortality rate and on the amount of fibrosis. The protective effect of lisinopril on heart function and on the degree of hypertrophy could only be detected in small infarcts

Central angiotensin converting enzyme-blockade and thirst

1. The effect of lisinopril, a potent inhibitor of angiotensin converting enzyme (ACE), injected into the medial preoptic area (MPOA) on water intake was investigated in male Holtzman rats (200-250 g). 2. Injection of lisinopril (2 micrograms/microliters) into the MPOA abolished the water intake induced by subcutaneous (sc) injection of isoprenaline (100 per cent ) and water deprivation (90 per cent ) and drastically reduced the water intake induced by sc injection of polyethyleneglycol (60 per cent ). A small reduction of water intake induced by lisinopril was also observed 90 and 120 min after sc hypertonic saline (N = 10 for each group). 3. These results suggest that central ACE activation, particularly in the MPOA, plays an important role in the dipsogenic responses induced by the agents studied