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.
Angiotensins ; Animals ; Captopril* ; Cysteine ; Depression ; Dithiothreitol ; Electrolysis ; Enalaprilat ; Free Radicals ; Heart ; Heart Rate ; Lipid Peroxidation ; Myocardial Ischemia ; Oxygen ; Rats ; Reperfusion Injury ; Superoxides ; Ventricular Pressure

OBJECTIVETo investigate effects of angiotensin (1-7) [Ang (1-7)] and enalaprilat on function of isolated rat heart perfused by burn serum.

METHODSEighty 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.

RESULTSCompared 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).

CONCLUSIONSAng (1-7) and enalaprilat can effectively improve left ventricular function of isolated rat heart perfused by burn serum and mitigate myocardial injury.

Angiotensin I ; pharmacology ; Animals ; Burns ; blood ; Enalaprilat ; pharmacology ; Male ; Myocardial Reperfusion Injury ; prevention & control ; Peptide Fragments ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Serum ; Ventricular Function, Left ; drug effects

OBJECTIVETo 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.

METHODSForty 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.

RESULTSCompared 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).

CONCLUSIONSingle 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.

Animals ; Burns ; drug therapy ; pathology ; Deslanoside ; administration & dosage ; Disease Models, Animal ; Drug Therapy, Combination ; Enalaprilat ; administration & dosage ; Male ; Random Allocation ; Rats ; Rats, Wistar ; Viscera ; pathology

OBJECTIVETo investigate the therapeutic effects of Enalaprilat on the myocardial kinetics in rats at early stage of severe scald.

METHODSEighty-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.

RESULTSThe 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].

CONCLUSIONMyocardium 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.

Animals ; Burns ; drug therapy ; physiopathology ; Dose-Response Relationship, Drug ; Enalaprilat ; pharmacology ; therapeutic use ; Myocardium ; pathology ; Rats ; Rats, Sprague-Dawley ; Ventricular Remodeling

OBJECTIVETo investigate the dose-effect relationship of enalaprilat (ENA) injection on the organ damage following early burn injury in rats.

METHODSA 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.

RESULTSAng 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).

CONCLUSIONLow-dose enalaprilat, injection (1 mg/kg) could alleviate organ damage in post-burned rats, but has little effect on AOSP and AODP.

Angiotensin-Converting Enzyme Inhibitors ; therapeutic use ; Animals ; Burns ; blood ; drug therapy ; pathology ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Enalaprilat ; therapeutic use ; Female ; Male ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Viscera ; drug effects ; pathology

OBJECTIVENeurogenic 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.

METHODNPE 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.

RESULTACE 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.

CONCLUSIONThe 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.

Angiotensin II ; genetics ; metabolism ; Angiotensin-Converting Enzyme Inhibitors ; pharmacology ; Animals ; Disease Models, Animal ; Enalaprilat ; pharmacology ; Female ; Fibrinogen ; pharmacology ; Gene Expression Regulation, Enzymologic ; Lung ; metabolism ; pathology ; Male ; Peptidyl-Dipeptidase A ; genetics ; metabolism ; Pulmonary Edema ; chemically induced ; metabolism ; pathology ; RNA, Messenger ; metabolism ; Rabbits ; Random Allocation ; Real-Time Polymerase Chain Reaction