Protective effect of an angiotensin-converting-enzyme inhibitor on neurogenic pulmonary edema in rabbits / 中华儿科杂志

<p><b>OBJECTIVE</b>Neurogenic pulmonary edema (NPE ) was indicative of poor prognosis in the epidemic of enterovirus 71 infections. The pathogenesis of NPE remains poorly understood. The objectives of this experimental study were to explore whether RAS is activated during NPE in rabbit models induced by fibrin and the effects of an angiotensin converting enzyme inhibitor (enalaprilat) on NPE.</p><p><b>METHOD</b>NPE models were induced by intracisternal injection of fibrinogen and thrombin. According to random number table method, 18 healthy adult New Zealand rabbits were assigned to three groups (with 6 in each) : normal control group (Con group), NPE group and enalaprilat treated (Ena) group. After establishment of NPE models, rabbits in Ena group were given intravenous enalaprilat 0.5 mg/kg. Expression of ACE,ACE2,AT1R mRNA of the lung tissue were evaluated by real-time polymerise chain reaction; and Ang II of the lung tissue was determined by enzyme linked immunosorbent assay ( ELISA ). Meanwhile, histopathological lung injury scores were evaluated.</p><p><b>RESULT</b>ACE mRNA expression level in NPE group ( 17.2 ± 3.3) appeared an increasing trend in contrast to Con group ( 12.6 ± 5.2 ) and Ena group ( 11.5 ± 2.4, both P > 0.05 ). Compared with Con group (81 ± 22 ), ACE2 mRNA expression levels of NPE group ( 52 ± 6 ) and Ena group ( 45 ± 13 ) both decreased ( both P < 0.05 ) . ACE mRNA/ACE2 mRNA expression levels of NPE group ( 0.33 ± 0.06 ) and Ena group ( 0.26 ± 0.04 ) were higher than those of Con group ( 0.16 ± 0.05, both P < 0.05 ), as well as the ratio of Ena group decreased compared with untreated NPE group ( 0.26 ± 0.04 vs. 0.33 ± 0.06, P < 0.05 ) . There were no statistically significant differences in expression of AT1 mRNA of the lung tissue among three groups, but Ena group ( 4.8 ± 1.1) in contrast to NPE group ( 6.7 ± 1.3) has no significant difference (P > 0.05). Lung AngII level of NPE group [(540 ± 147) pg/ml] was significantly higher than that of Con group [(253 ± 37 ) pg/ml] and Ena group [(309 ± 35 ) pg/ml, both P < 0.05 ]. Gross pathologic examination showed that pink foamy edema fluid appeared in the tracheal tubes in NPE group, but spontaneously appeared in neither Con group nor Ena group; and the level of pulmonary subpleural bleeding in Con group, 12 graded 0; in NPE group, 2 graded II, 10 graded III; in Ena group, 2 graded, 8 grade II, 2 grade III. The histopathologic lung injury scores in Ena group was decreased in contrast to NPE group (1.36 ± 0.26 vs.2.32 ± 0.49, P < 0.05) and mainly for the improvement of alveolar overdistension and interstitial edema.</p><p><b>CONCLUSION</b>The present study showed that when NPE occurs, a high lung AngII concentration was associated with an imbalance between ACE mRNA to ACE2 mRNA expression level. Activated local RAS in lung tissue resulted in lung injury. Enalaprilat treatment may attenuate lung injury by interventing local RAS in lung tissue with decreased ratio of ACE mRNA to ACE2 mRNA and lung AngII concentration. The result will be significant for the angiotensin converting enzyme inhibitor used in the theatment of NPE.</p>

Gadolinium increases the vascular reactivity of rat aortic rings

Gadolinium (Gd) blocks intra- and extracellular ATP hydrolysis. We determined whether Gd affects vascular reactivity to contractile responses to phenylephrine (PHE) by blocking aortic ectonucleoside triphosphate diphosphohydrolase (E-NTPDase). Wistar rats of both sexes (260-300 g, 23 females, 7 males) were used. Experiments were performed before and after incubation of aortic rings with 3 µM Gd. Concentration-response curves to PHE (0.1 nM to 0.1 mM) were obtained in the presence and absence of endothelium, after incubation with 100 µM L-NAME, 10 µM losartan, or 10 µM enalaprilat. Gd significantly increased the maximum response (control: 72.3 ± 3.5; Gd: 101.3 ± 6.4 percent) and sensitivity (control: 6.6 ± 0.1; Gd: 10.5 ± 2.8 percent) to PHE. To investigate the blockade of E-NTDase activity by Gd, we added 1 mM ATP to the bath. ATP reduced smooth muscle tension and Gd increased its relaxing effect (control: -33.5 ± 4.1; Gd: -47.4 ± 4.1 percent). Endothelial damage abolished the effect of Gd on the contractile responses to PHE (control: 132.6 ± 8.6; Gd: 122.4 ± 7.1 percent). L-NAME + Gd in the presence of endothelium reduced PHE contractile responses (control/L-NAME: 151.1 ± 28.8; L-NAME + Gd: 67.9 ± 19 percent AUC). ATP hydrolysis was reduced after Gd administration, which led to ATP accumulation in the nutrient solution and reduced ADP concentration, while adenosine levels remained the same. Incubation with Gd plus losartan and enalaprilat eliminated the pressor effects of Gd. Gd increased vascular reactivity to PHE regardless of the reduction of E-NTPDase activity and adenosine production. Moreover, the increased reactivity to PHE promoted by Gd was endothelium-dependent, reducing NO bioavailability and involving an increased stimulation of angiotensin-converting enzyme and angiotensin II AT1 receptors.

Effects of angiotensin (1-7) and enalaprilat on function of isolated rat heart perfused by burn serum / 中华烧伤杂志

<p><b>OBJECTIVE</b>To investigate effects of angiotensin (1-7) [Ang (1-7)] and enalaprilat on function of isolated rat heart perfused by burn serum.</p><p><b>METHODS</b>Eighty SD rats were used to prepare burn serum. Hearts of another 24 SD rats were isolated to reproduce Langendorff perfusion model. The rat hearts were divided into different groups with different perfusion fluids as K-H buffer group, K-H buffer containing 20% burn serum group (burn serum group), K-H buffer containing 20% burn serum and 2 microg/mL enalaprilat group (enalaprilat group), and K-H buffer containing 20% burn serum and 1 nmol/mL Ang (1-7) group [Ang(1-7) group]. The rat hearts were perfused for 30 mins with each of above-mentioned fluids in different groups. Then left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), +/- dp/dt max, coronary flow(CF), level of creatine kinase (CK) and lactate dehydrogenase (LDH) in respective coronary effluent were determined.</p><p><b>RESULTS</b>Compared with LVSP (11.2 +/- 1.0 kPa, 1 kPa = 7.5 mm Hg), +dp/dt max (642 +/- 53 kPa/s), -dp/dt max (380 +/- 61 kPa/s) and CF level in K-H buffer group, CF, LVSP (5.9 +/- 0.8, 8.0 +/- 1.1, 8.9 +/- 1.3 kPa, respectively), +dp/dt max (275 +/- 37, 454 +/- 48, 479 +/- 63 kPa/s, respectively), -dp/dt max (135 +/- 35, 219 +/- 47, 277 +/- 58 kPa/s, respectively) of burn serum group, those levels in Ang (1-7) group, and enalaprilat group were decreased obviously (P < 0.05 or P < 0.01), but LVEDP, level of CK and LDH in coronary effluent were increased. Compared with those parameters in burn serum group, CF, LVSP, +/- dp/dt max of Ang (1-7) group and enalaprilat group were increased obviously (P < 0.05 or P < 0.01), and LVEDP, level of CK and LDH in coronary effluent were decreased obviously (P < 0.01).</p><p><b>CONCLUSIONS</b>Ang (1-7) and enalaprilat can effectively improve left ventricular function of isolated rat heart perfused by burn serum and mitigate myocardial injury.</p>

Enalaprilat induced acute parotitis.

Drug induced acute parotitis is a very uncommon complication reported with a few drugs only. There is no case of acute bilateral parotitis reported previously with i.v. enalaprilat. We present here a female patient who developed acute bilateral parotitis within minutes of i.v. enalaprilat injection and recovered within 24 hours of stopping the drug and with symptomatic treatment.

Protective effects of enalaprilat on the myocardial kinetics in rats at early stage of severe scald / 中华烧伤杂志

<p><b>OBJECTIVE</b>To investigate the therapeutic effects of Enalaprilat on the myocardial kinetics in rats at early stage of severe scald.</p><p><b>METHODS</b>Eighty-four SD rats were inflicted with 30% TBSA full-thickness scald, and randomly divided into scald (S, with intraperitoneal injection of isotonic saline according to Parkland formula, n=30), L (n=30), M (n=12) and H (n=12) groups. The rats in L,M,H groups were intraperitoneally injected with 1,2,4 mg/kg Enalaprilat. Other 6 healthy rats were enrolled into study as control (C group). The myocardial kinetic parameters including left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), +/- dp/dt max and the levels of A II in myocardium were observed at 1,3,6,12 and 24 post scald hour (PBH) in L and S groups,and at 6,12 PBH in M and H groups. The above indices in C group were also examined.</p><p><b>RESULTS</b>The levels of LVSP, LVEDP, +/- dp/dt max in C group were higher than those in other groups during 3-24 PBH (P < 0.05 or P < 0.01), while those in L,M,H groups were obviously higher than those in S group (P < 0.05 or P < 0.01). The level of +/- dp/dt max in H group at 6,12 PBH were obviously lower than those in L and M groups. The level of A II in S group at 1 PBH was (53.0 +/- 2.6) pg/200 mg, which was significantly higher than thatin C group [(14.8 +/- 0.7) pg/200 mg, P < 0.05 or P < 0.01]; it peaked at6 PBH and lowered afterwards, and they were significantly higher than that in C group at 24 PBH (P < 0.01). The levels of A II in L group during 3-24 PBH were obviously higher than those in C group (P < 0.01), which were also lower than those in S group. The level of A II in S group was significantly higher than in L,M,H groups at 6 PBH [(145.2 +/- 14.5) pg/200 mg. vs. (65.1 +/- 0.9) pg/200 mg, (53.6 +/- 1.1) pg/200 mg, (34.2 +/- 0.9) pg/200 mg, respectively, P < 0.01].</p><p><b>CONCLUSION</b>Myocardium can be obviously damaged at early stage after severe scald,cardiac function is impaired. Enalaprilat injection (especially at low dose) can significantly ameliorate the myocardial kinetics indices, and it seems to exert a protective effect on cardiac function.</p>

Protective effect of enalaprilat injection against early postburn organ damage in rats / 中华外科杂志

<p><b>OBJECTIVE</b>To investigate the dose-effect relationship of enalaprilat (ENA) injection on the organ damage following early burn injury in rats.</p><p><b>METHODS</b>A total of 54 SD rats were subjected to 30% total body surface area III scald injury, and were randomly divided into simple scald group (B group, with conventional fluid transfusion after scald), ENA treated group (E1, E2, E3 group, with intraperitoneal enalaprilat injection of 1, 2, 4 mg/kg after scald respectively). Other 6 rats were taken as normal control. Aortic systolic pressure (AOSP), aortic diastolic blood pressure (AODP), mean arterial pressure (MAP), angiotensin 1, blood urea nitrogen (Bun), creatinine (Cr), creatinine kinase (CK), alanine aminotransferase (ALT), aspartate aminotransferase (AST) of the simple scald group, E1 group, E2 group and E3 group were investigated at 6 h and 12 h post burn.</p><p><b>RESULTS</b>Ang II, Bun, Cr, CK, ALT, AST levels in ENA treated group after 6 h and 12 hours were significantly lower than those of simple scald group (all P < 0.05). AOSP, AODP, MAP in ENA treated group after 6 and 12 hours were significantly higher than those of simple scald group (all P < 0.05).</p><p><b>CONCLUSION</b>Low-dose enalaprilat, injection (1 mg/kg) could alleviate organ damage in post-burned rats, but has little effect on AOSP and AODP.</p>

Effects of single or combined administration of cedilanid and enalaprilat on visceral damages in early stage of severe scald in rats / 中华烧伤杂志

<p><b>OBJECTIVE</b>To investigate the effects of single or combined administration of cedilanid and small-dose of enalaprilat on heart, liver, kidney and intestine damages at early stage of severe scald in rats.</p><p><b>METHODS</b>Forty healthy male Wistar rats were enrolled in the study and randomly divided into: sham, burn control, cedilanid, enalaprilat, cedilanid + enalaprilat groups, with 8 rats in each group. Rats, except that of sham group (simulated scald with 37 degrees C water) were inflicted with 30% TBSA full-thickness scald, and were injected with Ringer's lactate solution (4 mLxkg(-1)x1% TBSA(-1)) intraperitoneally 30 minutes after burn. Then rats in cedilanid group were given cedilanid injection (0.2 mg/kg) intravenously, and those in enalaprilat group were given enalaprilat (1 mg/kg), and cedilanid + enalaprilat group with cedilanid and enalapril in the same dosage. At 6 post burn hour (PBH) or sham injury, parameters of myocardiac mechanics were recorded with the Multiple Channel Physiological Signal Collecting and Processing System. The blood flow of the liver, kidney and intestine was respectively detected with the Laser Doppler Flowmetry at 6 PBH. Serum contents of cTnI, TBA, beta2-MG and DAO were determined at 6 PBH to reflect visceral damages.</p><p><b>RESULTS</b>Compared with those in sham group, the parameters of myocardiac mechanics and blood flow of liver, kidney, intestine (158 +/- 32, 156 +/- 46, 119 +/- 30 PU, respectively) in burn control group were obviously decreased (P < 0.05), and the serum contents of cTnI, TBA, beta2-MG, DAO (5.0 +/- 0.3 microg/L, 82 +/- 23 micromol/L, 2.55 +/- 0.15 mg/L, 1.52 +/- 0.08 kU/L, respectively) in burn control group were obviously increased (P < 0.05). Compared with those in burn control group, the parameters of myocardiac mechanics and blood flow of liver, kidney, intestine in the cedilanid or enalaprilat groups increased markedly, and their serum contents of cTnI, TBA, beta2-MG, DAO decreased significantly (P < 0.05). Compared with those in burn control group, the parameters of myocardiac mechanics and blood flow of liver, kidney, intestine (240 +/- 49, 239 +/- 75, 194 +/- 55 PU, respectively) in cedilanid + enalaprilat group increased significantly (P < 0.05), and the serum contents of cTnI, TBA, beta2-MG, DAO (3.43 +/- 0.21 microg/L, 47 +/- 8 micromol/L, 2.01 +/- 0.16 mg/L, 1.17 +/- 0.15 kU/L, respectively) were decreased (P < 0.05).</p><p><b>CONCLUSION</b>Single administration of cedilanid or small-dose enalaprilat can ameliorate impairment of cardiac functions, prevent damages to liver, kidney and intestine in early stage of severe scald in rats. Combined administration of cedilanid and small-dose enalaprilat seems to be more effective.</p>

Aspectos morfológicos produzidos pelo enalaprilato no miocárdio, diagrama e gastrocnêmio induzidos pelo isoproterenol / Morphological aspects produced by isoproterenol-induced enalaprilat in the myocardium, diaphragm and gastrocnemius muscle of rats

Objetivo: Avaliar o efeito do enalaprilato, inibidor da enzima conversorade angiotensina, no processo de reversão da hipertrofia, uma vez quea hipertrofia ventricular esquerda é um importante fator fisiológicopreditivo que auxilia na prevenção de doenças cardíacas, pois seusmecanismos indutores estão relacionados ao índice de massa corporal,hipertensão, hipercolesterolemia, tabagismo, diabetes e uso demedicação, que são empregados nos índices para modelos de avaliaçãode risco. Métodos: Um modelo histomorfométrico comparativo foiempregado para analisar os miócitos do ventrículo esquerdo, diafragmae gastrocnêmio. Oitenta ratos Wistar foram divididos em cinco grupos:controle, isoproterenol, enalaprilato, isoproterenol-enalaprilato (ISOE)e isoproterenol-água. O coração, o diafragma e o gastrocnêmioforam submetidos a uma análise histomorfométrica microscópica.Resultados: A proporção da massa tecidual úmida-seca verificouseaumentada entre os grupos controle e isoproterenol. Não houvediferença estatística significativa ou morfológica entre os demaisgrupos experimentais. Conclusão: Sugere-se que há forte evidênciade que a hipertrofia ventricular esquerda seja primariamente induzidapor ativadores neuro-humorais relacionados aos sistemas simpáticoe renina-angiotensina. O enalaprilato aumenta a taxa de regressãohipertrófica no ventrículo esquerdo, mas isto não é observado nodiafragma e gastrocnêmio.

Systemic and regional hemodynamic effects of enalaprilat infusion in experimental normotensive sepsis

Angiotensin-converting enzyme inhibitors have been shown to improve splanchnic perfusion in distinct shock states. We hypothesized that enalaprilat potentiates the benefits of early fluid resuscitation in severe experimental sepsis, particularly in the splanchnic region. Anesthetized and mechanically ventilated mongrel dogs received an intravenous infusion of live Escherichia coli over a period of 30 min. Thereafter, two interventions were performed: fluid infusion (normal saline, 32 mL/kg over 30 min) and enalaprilat infusion (0.02 mg kg-1 min-1 for 60 min) in randomized groups. The following groups were studied: controls (fluid infusion, N = 4), E1 (enalaprilat infusion followed by fluid infusion, N = 5) and E2 (fluid infusion followed by enalaprilat infusion, N = 5). All animals were observed for a 120 min after bacterial infusion. Mean arterial pressure, cardiac output (CO), portal vein blood flow (PVBF), systemic and regional oxygen-derived variables, and lactate levels were measured. Rapid and progressive reductions in CO and PVBF were induced by the infusion of live bacteria, while minor changes were observed in mean arterial pressure. Systemic and regional territories showed a significant increase in oxygen extraction and lactate levels. Widening venous-arterial and portal-arterial pCO2 gradients were also detected. Fluid replacement promoted transient benefits in CO and PVBF. Enalaprilat after fluid resuscitation did not affect systemic or regional hemodynamic variables. We conclude that in this model of normotensive sepsis inhibition of angiotensin-converting enzyme did not interfere with the course of systemic or regional hemodynamic and oxygen-derived variables.

Interference of enalaprilat on glomerular permeability to macromolecules (IGG) in acute unilateral ureteral obstruction in rats

INTRODUCTION: Unilateral ureteral obstruction breaks out events that cause the transitory increase of glomerular permeability to macromolecules, both in the obstructed kidney and in the contralateral kidney, suggesting the presence of some factor, with a systemic action, liberated as a response to the obstruction. We know that the rennin-angiotensin system is activated by acute ureteral obstruction. We have developed an experiment to assess the role of angiotensin II on the glomerular permeability to IgG due to acute ureteral obstruction, using enalaprilat, an angiotensin enzyme conversion inhibitor, to block the effects of the activation of the rennin-angiotensin system. MATERIALS AND METHODS: We have used 45 adult Wistar female rats, distributed into 3 main groups: a control group with 5 animals and 2 experiment groups each one with 10 animals submitted to unilateral ureteral obstruction and nephrectomy at 60 and 120 minutes. Each experiment group had its simulation correspondent (sham). We have studied both kidneys through the direct immunofluorescence method. RESULTS: We have found positive permeation in animals without enalaprilat in both kidneys and negative permeation in those in which the drug was used. CONCLUSION: We have concluded that enalaprilat interferes in this alteration of permeability, suggesting that angiotensin II is involved in the loss of selectivity of the glomerular membrane.

Evaluation of the efficacy, safety and tolerability of intravenous enalaprilat in the treatment of grade III essential hypertension in Indian patients.

Hypertensive emergency is a common problem requiring an effective, safe and easily administrable agent to reduce the blood pressure. Favorable data on injectable enalaprilat have been reported from the West but no Indian study has been done in such settings. We studied 10 patients (5 male, 5 female), with mean age 47+/-0.6 years and mean blood pressure 196+/-18.95/119.4+/-19.53 mmHg, who were given 1.25 mg intravenous enalaprilat. Reduction in their blood pressure started at 5 min with peak reduction noted at 4 hours (155.25+/-29.54/93.5+/-13.55 mmHg). No adverse symptoms or biochemical changes were noted. Thus, we conclude that intravenous enalaprilat is an effective, safe and well tolerated agent for managing severe hypertension in patients requiring an emergency reduction in blood pressure.

Relative bioavailability study of 20-mg enalapril tablets in healthy male volunteers.

The pharmacokinetic and relative bioavailability studies of 20-mg enalapril tablets, the test product manufactured by Biolab, Thailand compared to the reference product (Merck Sharp & Dohme, USA) was conducted in 14 healthy Thai male volunteers following a single dose, two-period, crossover design. Each subject received 20-mg enalapril tablets of both formulations with a 1-week washout period. Plasma samples collected over a 24-h period after administration were analyzed by LC/MS/MS. Pharmacokinetic parameters were determined by using non-compartmental analysis. Regarding bioequivalence testing, the 90 per cent confidence intervals of Cmax and AUC(0-infinity) ratios (test/reference) of enalapril were 101.8-134.9 per cent and 105.9-121.4 per cent and those of enalaprilat were 104.2-122.3 per cent and 104.5-118.1 per cent. Based on the European bioequivalence guideline, the 90 per cent confidence intervals of Cmax and AUC(0-infinity) ratios of both parent and metabolite forms were within the acceptable ranges of 70-143 per cent and 80-125 per cent, respectively. It was concluded that the test formulation was bioequivalent to the reference formulation and both formulations can be used interchangeably in clinical practice.

Efeitos histomorfométricos do enalaprilato na hipertrofia do ventrículo esquerdo, diafragma e musculatura periférica de ratos, induzida pelo isoproterenol / Histometric effects of enalaprilat in left hypertrophy, diaphragm and peripheral muscle in rats, induced by isoproterenol

A hipertrofia ventricular esquerda (HVE) é o mais tormentoso fator de risco cardiovascular, cursando de modo independente dos demais. Para prevenção primária e secundária é necessário elucidar os mecanismos de indução. Objetivos: Estudar o efeito do enalaprilato na reversão da hipertrofia ventricular esquerda, do diafragma e do gastrocêmio para contribuir na elucidaçâo dos mecanismos de indução da HVE. Material e métodos: foram estudados 80 ratos Wistar e divididos em 5 grupos: Grupo Controle (CON): ratos submetidos por oito dias consecutivos a injeções subcutâneas de O,3 ml de óleo de oliva às 8.OOh, e em seguida 22 dias consecutivos de injeções subcutâneas de O,3 ml de água destilada às 8.00 h. Grupo Isoproterenol (ISO): ratos submetidos por oito dias consecutivos a injeções subcutâneas às 8.00 h, de suspensão em óleo de oliva de O,3 mg/kg de peso de isoproterenol (Sigma Co.). Grupo Isoproterenol-Água (ISO-ÁGUA): ratos submetidos por oito dias consecutivos a injeções subcutâneas de suspensão em óleo de oliva, de O,3 g/kg de peso isoproterenol (Sigma Co) às 8.00 h, e em seguida, 22 dias onsecutivos de injeções subcutâneas de O,3 ml de água destilada, às 8.00 h; Grupo Isoproterenol-Enalapriiato (ISO-ENA): ratos submetidos por oito dias consecutivos a injeções subcutâneas, de suspensão em óleo de oliva de O,3 g/kg de peso de isoproterenol (Sigma Co) às 8.00 h, e em seguida, 22 dias consecutivos de injeções subcutâneas de O,3 ml de enalaprilato (lote L 072314-Merck Sharp & Dohme), às 8.00 h; Grupo Enalaprilato (ENA): ratos submetidos por oito dias consecutivos a injeções subcutâneas de O,3ml de óleo de oliva às 8.00 h, e em seguida, 22 dias consecutivos de injeções subcutâneas de O,3 ml de enalaprilato (lote L 072314-Merck Sharp & Dohme), às 8.00 h. Ao final do experimento os animais eram sacrificados e analisado o coração, diafragma e o gastrocnêmio. Foi feita a histometria dos três tipos de miócitos, e obtido o peso seco e úmido do VE nos cinco grupos. Peso úmido: ISO > ISO-ÁGUA = ISO-ENA > CON = ENA Peso seco: ISO > ISO-ÁGUA = ISO-ENA > CON = ENA Resultado da histometria das Fibras Musculares Cardíacas, Diafragmáticas e do Gastrocnêmio em centímetros: Para os eixos maiores e eixos menores do VE: ISO > ISO-ÁGUA > CON = ISO-ENA = ENA ISO > ISO-ÁGUA > CON = ISO-ENA = ENA Para os eixos maiores e eixos menores do diafragma e do gastrocnêmio: ISO > ISO-ÁGUA = ISO-ENA = ENA = CON Conclusões: considerando os mecanismos...(au)

Efecto del enalaprilato sobre la disfuncion postisquemica sistolica y diastolica (miocardio atontado) en el corazon aislado de conejo / Effect of enalaprilat on postischemic systolic and diastolic dysfunction (stunned myocardium) on the isolated rabbit heart

El objetivo principal del trabajo fue determinar en el corazón aislado de conejo el efecto del Enalaprilato administrado: a) antes de la isquemia y b) en el momento de la reperfusión, sobre la función sistólica y diastólica del "miocardio atontado", y también sobre la fase de "hiperfunción" que ocurre precozmente en la reperfusión. Un segundo objetivo fue determinar si el enalaprilato modifica la liberación de lactato, creatinfosfoquinasa (CPK) y lacticodeshidrogenasa (LDH), que ocurre en el "miocardio atontado". Para esto utilizamos corazones de conejo perfundidos con la técnica de Langendorff, sometidos a isquemia global de 15 min y reperfusión durante 30 min y en los que la colocación de un globo de látex en el ventrículo izquierdo permitió medir la presión ventricular, y calcular la presión desarrollada, la maxima velocidad de ascenso y descenso de la presión (+ DP/dtmaxy -dP/dtmax, respectivamente), el cociente entre estas dos variables de velocidad (+ P/-P), y la constante de tiempo dirante la caída de la presión venricular (tau, tau). El Enalaprilato administrado tanto antes de la isquemia, como al comienzo de la reperfusión, atenúo la disfunción postisquémica sistólica, y la fase precoz de "hiperfunción". El efecto sobre la función diastólica fue diferente según se considere el componente activo o el pasivo: mientras que no modificó las lteraciones la relajación, atenuó significantemente el aumento de la rigidez miocárdica. El Enalaprilato también disminuyó la cantidad de lactato en el efluente durante la reperfusión, pero no modificó la liberación de CPK y LDH.

Enalaprilato na prevençäo da hipertrofia ventricular esquerda induzida pelo isoproterenol / Enalaprilat prevents the left ventricular hypertrophy induced by isoproteronol

OBJETIVO: Avaliar se o enalaprilato, droga inibidora da enzina de conversäo da angiotensina I, previne a hipertrofia ventricular esquerda (HVE) induzida pelo isoproterenol. MÉTODOS: Foram divididos em 4 grupos, 72 ratos Wistar-EPM: CON controle; ENA, tratados com enalaprilato ( 1 mg/kg via subcutânea (sc) por 8 dias); ISO, tratados com isoproterenol (0,3 mg/kg via sc/8 dias) e ENA+ISO, tratados simultaneamente com ambas as drogas. Em 10 animais de cada grupo foram determinadas a freqüência cardíaca (FC) e a pressäo arterial (PA) e verificado o peso de ventrículo esquerdo (VE). Em 8 animais de cada grupo, fragmento do VE foi corado com hematoxilia-eosina e picro-sírius e preparado para estudo morfométrico e ultra-estrutural, respectivamente, com microscópio de luz e eletrônico. RESULTADOS: Nos grupos estudados (CON, ENA, ISO e ISO+ENA) näo ocorreram variaçöes na PA. Os grupos ISO e ISO+ENA exibiram aumentos significantes na FC. O grupo ISO apresentou aumento significantivo do peso do VE(PU=0,821g e PS=0,204g), quando comparado ao grupo CON. O grupo ENA näo exibiu modificaçäo de peso do VE quando comparado ao grupo CON (PU=0,590g e PS=0,139g). No grupo ENA+ISO (PU=0,737g e PS=0,177g) constatou-se diferença de peso ao ser comparado aos grupos ISO e CON. A análise morfométrica e ultra-estrutural mostraram que o ISO induziu hipertrofia dos cardiomiócitos e aumento do tecido do tecido conjuntivo com depósito de fibras colágenas do tipo I. O enalaprilato associado com isoproterenol atenuou importantemente aquela manifestaçäo. CONCLUSÄO: O enalaprilato inibiu a açäo do isoproterenol sobre os cardiomiócitos, evitando parcialmente, na dose utilizada, a HVE e diminuindo também a quantidade de fibras colágenas.

Efeito do enalaprilato na cardiotoxidade induzida pela doxorubicina / Effect of enalaprilat on cardiotoxicity induced by doxorubicin

PURPOSE: To evaluate whether the enalaprilat, an angiotensin converting enzyme inhibitor, was able to prevent the myocardial damage induced by doxorubicin (DOX). METHODS: Four groups composed of 10 Wistar rats each were followed for seven weeks: control (CONT); treated with enalaprilat (ENA, 1mg/kg/d/sc) treated with doxorubicin (DOX, 25 mg/kg/d/sc), and treated with doxorubicin plus enalaprilat (DOX+ENA). In eight animals of each group, the left ventricle (LV) was prepared for morphometric study and stained with HE and picro-sírius for identifying muscle fibers and collagen. In each group three fragments of the LV were examined with electronic microscopy (EM). For statistical analysis: the one-way analysis of variance was performed and was followed by multiple comparisons test when the difference between groups were detected p values < or = 0.05 were considered significant. RESULTS: Light microscopy-it was not found any significant difference among the groups for muscle fibers patterns and proportion of collagen fibers of left ventricle. Electronic microscopy-the cristolysis index (proportion between normal and damage mitochondria) demonstrated significant difference between DOX and DOX+ENA groups (30.1 vs 11.6, p < or = 0.01). CONCLUSION: ENA prevented cardiotoxic alterations induced by DOX minimizing the aggression to the mitochondria and these findings, if confirmed in anima nobilis, may open a new clinical use for this type of drug.

Cardioprotective Effect of Captopril on Myocardial Oxidative Damage

BACKGROUND: Reactive oxygen free radicals have been implicated as an important factor in the development of ischemia-reperfusion injury of heart. Captopril, a SH-containing angiotensin converting enzyme(ACE) inhibitor has been reported to provide the protective effect in different models of myocardial ischemia and reperfusion injury of animal hearts. It is postulated that the myocardial protective effect may be related to a potential anti-free radical effect independent of ACE inhibition. The present study was designed to elucidate the myocardial protective mechanism of Captopril by investigating the drug effect on the experimentally induced oxygen free radical-mediated myocardial injury in isolated hearts of rats. METHODS: The heart isolated from rat was perfused retrogradly by Langendorff method. Myocardial dysfuntion was induced by oxygen free radicals generated by electrolysis of the perfusing solution(Kreb-Henseleit) with 2mA direct current for 45 sec. The cardiac functions(left ventricular pressure, dP/dt, heart rate, coronary flow) and the ventricular content of a lipid peroxidation product, malondialdehyde(MDA) were measured under presence of absence of Captopril and the compairing drugs(enalaprilat, cysteine and dithiothreitol). RESULTS: Electrolysis of oxygen-saturated Krebs-Henseleit perfusing solution led to the production of superoxide anion increasingly with intensity and duration of the applied electric current. The hearts perfused with the electroyzed solution demonstrated significant decrease in left ventricular pressure, dp/dt, heart rate, coronary folw and increase in myocardial MDA content. The depression of myocardial function as well as the increase of MDA content and oxygen radical production were reversed by Captopril(0.75~2mM) dose-dependently. Enalaprilat, a non-SH containing ACE inhibitor, however, showed no protective effect at all. Cysteine and dithiothreitol, the SH-containing agents without ACE inhibitory action showed also protective effects on the myocardial depression induced by electrolysis. CONCLUSION: It is suggested that Captopril may exert protective effect on oxygen radical-mediaed myocardial injury probably by its antioxidative and anti-free radical mechanism related to SH-group.