Comparison of captopril and enalapril to study the role of the sulfhydryl-group in improvement of endothelial dysfunction with ACE inhibitors in high dieted methionine mice

To examine the role of sulfhydryl (-SH) group in improvement of endothelial dysfunction with angiotensin-converting enzyme (ACE) inhibitors in experimental high dose of methionine dieted rats. We compared the effects of Captopril (an ACE inhibitor with -SH group), enalapril (an ACE-inhibitor without -SH group), N-acetylcysteine (only -SH group not ACE inhibitor) on endothelial dysfunction injured by methionine-induced hyperhomocysteinemia (HHcy) in rats. Male Sprague-Dawley rats were divided randomly into seven groups: control group, L-methionine group, low dose Captopril (15 mg/kg), middle dose Captopril (30 mg/kg), high dose Captopril (45 mg/kg), enalapril (20 mg/kg), N-acetylcysteine (200 mg/kg); control group were intragastric gavaged by water and others groups were intragastric gavaged by L-methionine and drugs in water one time every day. Acetylcholine (ACh)-induced endothelium-dependent relaxation (EDR), sodium nitroprusside (SNP)-induced endothelium-independent relaxation of aortic rings were examined. Paraoxonase1 (PON1) and ACE activity, malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD) in serum were analyzed. It was found that a single intragastric gavage by L-methionine resulted in inhibition of endothelium-dependent relaxation, markedly increased the serum level of malondialdehyde and decreased the activity of PON1 and SOD, similarly decreased the level of NO in the serum; but had no effects on endothelium-independent relaxation and angiotensin-converting enzyme activity compared with the control group. Given the treatment with three doses of Captopril (15 approximately 45 mg/kg) markedly attenuated inhibition of vasodilator responses to ACh, and eliminated the increased level of malondialdehyde, the decreased level of NO, activity of PON1 and SOD in serum by single intragastric gavaged L-methionine. However, there were some significant differences among Captopril (30 mg/kg or 45 mg/kg), enalapril (20 mg/kg), and N-acetylcysteine particular in the activity of PON1 and ACE. These results suggested that Captopril can protect the vascular endothelium against the damages induced by L-methionine in rats, and the beneficial effects of Captopril may be related to attenuating the decrease in PON1 activity and NO levels. Furthermore, this protective effect may be concerned with the sulfhydryl group.     

The protective effect of captopril on nicotine-induced endothelial dysfunction in rat

This study was designed to examine the in vivo and in vitro effects of captopril, an angiotensin-converting enzyme inhibitor, on nicotine-induced endothelial dysfunction in rats. Endothelial dysfunction was induced by exposing isolated rat mesenteric arteries to nicotine (0.01, 0.1, or 1 mM) for 24 hr using an organ culture system, or by treating rats with nicotine (2 mg/kg/day, intraperitoneally) for 4 weeks. The protective effects of captopril were tested by exposing isolated mesenteric arteries to captopril (0.01, 0.03, or 0.1 mM) + nicotine (0.1 mM) for 24 hr, or by treating rats with captopril (3 mg/kg/day, intravenously) + nicotine (2 mg/kg/day, intraperitoneally) for 4 weeks. Exposure of the isolated mesenteric arteries to nicotine induced a significant concentration -dependent inhibition of endothelium-dependent relaxation. Co-culture of segments of mesenteric artery with captopril (0.03 or 0.1 mM) attenuated the nicotine-induced impairment of vasorelaxation in a dose-dependent manner. Administration of nicotine to rats for 4 weeks significantly impaired endothelium-dependent relaxation compared with control rats. This impairment was accompanied by a reduction in nitrite/nitrate, nitric oxide (NO) synthase (NOS), and superoxide dismutase (SOD) activities in the serum and aorta. Chronic captopril treatment not only improved the impairment of endothelium-dependent relaxation, but also prevented the reduction of nitrite/nitrate contents and of NOS and SOD activities in the serum and aorta. However, there were no significant differences in serum angiotensin-converting enzyme activity among the three groups. These results indicate that captopril can be used to attenuate nicotine-induced endothelial dysfunction, an effect that may be related not only to antioxidation, but also to enhancing NO production by preventing the decrease in NOS.     

卡托普利对蛋氨酸所致血管内皮功能损伤的保护作用与对氧磷酶1的关系

目的探讨卡托普利对高蛋氨酸饮食所致大鼠血管内皮功能损伤的保护作用及其机制。方法将蛋氨酸通过灌胃的方法,1次.d-1,连续4周,诱导大鼠血管功能损伤,治疗组同时给予卡托普利、依那普利、N-乙酰半胱氨酸灌胃。4周后处死动物,检测血清一氧化氮(nitric oxide,NO)、丙二醛(malondialdehyde,MDA)含量、对氧磷酶(paraoxonase 1,PON1)、超氧化物歧化酶(superoxide dismutase enzyme,SOD)、血管紧张素转换酶(an-giotensin-converting enzyme,ACE)活性。取胸主动脉检测由乙酰胆碱(acetylcysteine,Ach)诱导的血管内皮依赖性舒张反应。结果高蛋氨酸损伤组大鼠血管内皮依赖性舒张反应显著减弱,血清中MDA浓度升高,PON1活性、血浆NO浓度与SOD活性降低;卡托普利、N-乙酰半胱氨酸和依那普利能显著改善血管内皮依赖性舒张反应、降低MDA浓度、提高血清中的PON1活性、SOD活性和NO浓度。结论卡托普利能够改善高蛋氨酸引起的血管内皮功能的损伤,该作用可能与保护PON1活性及其抗氧化作用、促进内皮细胞释放NO有关。     

卡托普利对甘油诱导的急性肾衰的保护作用及其机制探讨

目的研究卡托普利对甘油诱导的横纹肌溶解性急性肾衰的保护作用及其机制。方法用50%（v/v）的甘油按8mL.kg^-1后肢肌内注射建立急性肾衰的动物模型。所有大鼠单笼饲养,药物处理组每日分别以卡托普利和依那普利灌胃共7d,第7d损伤组和药物处理组禁水24h后注射甘油,注射甘油后饮水不限,24h后处死动物。通过检测血浆晚期氧化蛋白产物（AOPP）水平、肾组织形态学变化、超氧化物歧化酶（SOD）、血管紧张素转换酶（ACE）和谷胱甘肽过氧化物酶（GSH-Px）活性等查明AOPP是否与急性肾衰有关,并阐明卡托普利对其的保护作用及其机制。结果给大鼠后肢肌内注射50%（v/v）的甘油能诱导横纹肌溶解性急性肾衰,降低SOD、GSH-Px的活性和NO浓度,升高血尿素氮（BUN）、肌酐（Cr）浓度、AOPP和脂质过氧化产物（MDA）水平。卡托普利（30mg·kg^-1）能减轻肾损害和改善肾功能,逆转SOD、GSH-Px的活性、NO和AOPP水平的改变,而依那普利（30mg·kg^-1）和低剂量的卡托普利（10mg·kg^-1）保护作用不明显。结论卡托普利（30mg·kg^-1）对横纹肌溶解所致急性肾衰具有明显的保护作用,该作用可能与其抗氧化作用有关,而且可能是巯基依赖性的。     

Two inhibitors of angiotensin-converting enzyme, enalapril and captopril, increase salt appetite of rats

Male rats were orally administered an inhibitor of angiotensin-converting enzyme (ACE), N-[(S)-1-(ethoxycarbonyl)-3-phenylpropyl]-1-ala-1-pro maleate (enalapril, MK-0421) at dosage levels of 10, 30, and 90 mg/kg X d. After 2-6 wk of dosing, the rats receiving 30 and 90 mg/kg X d produced large numbers of seminal plugs and had lacerated penises due to licking in an attempt to recover urine. Providing 0.9% saline as the source of drinking water prevented this behavior and subsequent lesions. There were no adverse effects on reproductive performance. A subsequent study showed that enalapril at 5 mg/kg X d po and captopril (another ACE inhibitor) at 25 mg/kg X d po increased NaCl intake in rats. Our results with captopril confirm those of Fregly (1980) and Evered and Robinson (1983) and show that both converting-enzyme inhibitors (enalapril and captopril) increase salt appetite in rats.     

Captopril restores endothelium-dependent relaxation induced by advanced oxidation protein products in rat aorta

To explore whether advanced oxidation protein products (AOPP) can cause endothelial dysfunction in vitro, and whether captopril exerts beneficial effect on impaired endothelium-dependent relaxation induced by exogenous advanced oxidation protein products and to investigate the potential mechanisms. Both the Acetylcholine (ACh)-induced endothelium-dependent relaxation (EDR), sodium nitroprusside-induced endothelium-independent relaxation of aortic rings were measured by recording isometric tension after the rings were exposed to AOPP-BSA in the absence or presence of captopril to assess the injury effect of AOPP-BSA and the protective effect of captopril on the aortic endothelium, respectively. Co-incubation of aortic rings with AOPP-BSA (3 mmol/L) for 90 minutes resulted in a significant inhibition of EDR to ACh, but had no effects on endothelium-independent relaxation to SNP. After incubation of the rings in the co-presence of captopril (3 to 30 micromol/L) or enalaprilat (30 micromol/L) with AOPP-BSA (3 mmol/L) for 90 minutes, captopril significantly and enalaprilat only partly attenuated the inhibition of EDR induced by AOPP-BSA. This protective effect of captopril (30 micromol/L) was abolished by N-nitro-L-arginine methyl ester (10 micromol/L), an inhibitor of nitric oxide synthase. Furthermore, the superoxide anion scavenger superoxide dismutase (SOD, 200 U/mL), and the nitric oxide precursor L-arginine (3 mmol/L) also ameliorated the impaired EDR caused by AOPP-BSA. But D-arginine had no effect on the impaired EDR caused by AOPP-BSA. AOPP-BSA can trigger endothelial dysfunction and captopril can protect the endothelium against functional damage induced by AOPP-BSA in rat aorta, increase nitric oxide bioavailability. The mechanisms of endothelial dysfunction induced by AOPP-BSA may include the decrease of NO and the generation of oxygen-free radicals.     

Effects of simvastatin on endothelial function after chronic inhibition of nitric oxide synthase by L-NAME

Blood pressure, plasma NO(2) and NO(3) level, heart weight index, antioxidant enzyme activity, and vascular reactivity in rat intact aortic rings were assessed to investigate the effects of 8-week treatment with the hydroxy-methyl-glutaryl coenzyme A reductase inhibitor simvastatin (1 mg/kg per day) on endothelial dysfunction induced by chronic Nomega-nitro-l-arginine methyl ester (l-NAME 70 mg/kg per day). Results were compared with those obtained in rats receiving l-NAME, simvastatin or control animals. Coadministration of simvastatin did not restore l-NAME-increased blood pressure but normalized heart weight index (P < 0.05), endothelium-dependent relaxation to acetylcholine (P < 0.001), and plasma NO(2) and NO(3) concentration (P < 0.001) without affecting relaxation to sodium nitroprusside. Endothelium-dependent relaxation in these animals was abolished by acute incubation with l-NAME, unaffected by thromboxane synthetase inhibitor and TXA(2)/PGH(2) receptor antagonist, ridogrel, and decreased by indomethacin. Simvastatin treatment also increased plasma NO(2)+NO(3) without affecting endothelial function, heart weight index, and blood pressure of control rats. The presence of superoxide dismutase (SOD) and catalase improved endothelial relaxation only in l-NAME-treated rats, but O(2)- generated by hypoxanthine and xanthine oxidase inhibited the relaxant effect in both l-NAME and simvastatin plus l-NAME-treated rats. SOD activity was increased in all groups receiving simvastatin. Long-term treatment with simvastatin restored l-NAME-induced endothelial dysfunction, probably by preventing nitric oxide decrease. Other effects of simvastatin, including release of compensating vasodilatory cyclo-oxygenase products and increased SOD activity, could also be involved.     

A reduction of endogenous asymmetric dimethylarginine contributes to the effect of captopril on endothelial dysfunction induced by homocysteine in rats

We examined whether captopril exerts beneficial effect on homocysteine-induced endothelial dysfunction in vivo and whether this effect of captopril is associated with a reduction of endogenous inhibitor of nitric oxide synthase (NOS) asymmetric dimethylarginine (ADMA) in rats. Male Sprague-Dawley rats were given intravenous injections of homocysteine (10 mg/kg/day) to induce endothelial dysfunction. Captopril treatment (3 mg/kg/day, i.v.) was taken in some rats after homocysteine administration. Endothelium-dependent relaxation was tested in aortic rings. Serum levels of ADMA, nitrite/nitrate, malondialdehyde (MDA), and creatinine were measured. Furthermore, superoxide dismutase activity in liver and angiotensin converting enzyme activity in serum were also assayed. Administration of homocysteine to rats for 4 weeks significantly impaired endothelium-dependent relaxation compared with control rats. This impairment of endothelium-dependent relaxation was accompanied by elevated serum concentration of ADMA and decreased serum content of nitrite/nitrate. Moreover, serum concentration of MDA was remarkably increased, whereas liver superoxide dismutase activity was decreased in homocysteine-treated group compared with control. Chronic captopril treatment not only improved the impaired endothelium-dependent relaxation, but also prevented the elevation of serum ADMA and MDA levels, as well as reduction of serum nitrite/nitrate contents and liver superoxide dismutase activity. Serum angiotensin converting enzyme activity and creatinine had no significant difference between the three groups. These results suggest that chronic captopril treatment reduces endogenous inhibitor of NOS in rats with homocysteine injection, which may contribute to the beneficial effect of captopril on homocysteine-induced endothelial dysfunction in vivo, and may be secondary to the antioxidative action of captopril.     

Captopril restores endothelium-dependent relaxation of rat aortic rings after exposure to homocysteine

This study was designed to investigate the effects of captopril, an angiotensin-converting enzyme inhibitor, on inhibition of endothelium-dependent relaxation induced by homocysteine in isolated rat aorta. Isometric tension recordings were used to assess inhibitory effects of homocysteine and protective effects of captopril on endothelium-dependent relaxation of aortic rings. Exposure of aortic rings to homocysteine (0.3 approximately 3 mmol/L) for 30 min induced a significant concentration-dependent inhibition of endothelium-dependent relaxation response to acetylcholine (ACh), but did not affect endothelium-independent relaxation response to sodium nitroprusside. Pre-incubation of aortic rings with captopril (3 approximately 30 micromol/L) for 15 min and co-incubation of aortic rings with homocysteine (1 mmol/L) for another 30 min attenuated the inhibition of homocysteine in a dose-dependent manner. Moreover, superoxide dismutase (SOD, 200 U/mL), a scavenger of superoxide anions, reduced homocysteine-induced inhibition. L-Arginine (3 mmol/L), a precursor of nitric oxide (NO), also attenuated the impairment of vasorelaxation induced by homocysteine. However, in the combined presence of SOD and L-arginine, the inhibitory effect of homocysteine was reversed, which was very similar to the effect of 30 micromol/L captopril. These results suggest that captopril can prevent the inhibition of endothelium-dependent relaxation induced by homocysteine in isolated rat aorta, which may be related to scavenging oxygen free radicals and enhancing NO production.     

Renin-angiotensin system blockade prevents the increase in plasma transforming growth factor beta 1, and reduces proteinuria and kidney hypertrophy in the streptozotocin-diabetic rat.

INTRODUCTION: Combination therapy with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) is used to improve renal outcome achieved by monotherapy in diabetic patients. In addition, interference with the renin-angiotensin system (RAS) reduced expression and excretion of transforming growth factor beta 1 (TGF-beta 1) in diabetic nephropathy. The aim of this study was to investigate the effects of interrupting the RAS by ACE inhibitor (ACE-I) or ARB monotherapy or by combination therapy on proteinuria, kidney hypertrophy and plasma TGF-beta 1 in diabetic rats. MATERIALS AND METHODS: Forty-one male Wistar rats were allocated to five groups: 1 = control rats, 2 = diabetic rats (streptozotocin [STZ] 55 mg/kg), 3 = diabetic rats as above receiving enalapril (20 mg/kg/day), 4 = diabetic rats receiving losartan (80 mg/kg/day), 5 = diabetic rats receiving both losartan and enalapril. The study lasted 60 days. RESULTS: Urinary protein excretion, kidney weight, serum ACE activity and plasma TGF-beta1 increased significantly in untreated diabetic rats compared with controls. Administration of losartan, enalapril, or both for 60 days prevented these changes. Furthermore, combined therapy for 30 days normalised urinary protein excretion, while monotherapy did not. Losartan inhibited serum ACE activity both in vivo and in vitro. Plasma TGF-beta 1 levels were positively correlated with blood glucose levels (r=0.4059) and with urinary protein excretion (r=0.3558). CONCLUSIONS: Combination therapy with losartan and enalapril was more effective than monotherapy with either drug in achieving an early antiproteinuric response. Long-term treatment with losartan was as effective as the combined treatment, possibly due to a dual inhibitory effect on the RAS. The antiproteinuric effect may be related, in part, to reduced TGF-beta 1.     

Dose-dependent effect of captopril on aortic reactivity of streptozotocin-diabetic rats

Diabetes mellitus is a primary risk factor for cardiovascular disorders. Strategies that interrupt the renin-angiotensin system have been known to reduce cardiovascular disease. The present study was performed to investigate the effect of sub-chronic administration of captopril on the aortic reactivity of streptozotocin-diabetic rats. Streptozotocin-diabetic rats received captopril (30 and 50 mg/kg per day) for 2 months. Contractile responses to phenylephrine (PE) and relaxation responses to acetylcholine (ACh) and isosorbide dinitrate (ISD) were obtained from aortic rings. Concentration-response curves from captopril-treated diabetic rats to PE were attenuated compared with vehicle (Saline)-treated diabetic rats, especially at a dose of 50 mg/kg captopril. In addition, endothelium-dependent relaxation responses induced by ACh were significantly higher in captopril-treated diabetic rats compared with diabetic rats. The endothelium-independent relaxation responses for ISD were found not to be significantly different among the groups. Therefore, sub-chronic treatment of diabetic rats with captopril in a dose-dependent manner could prevent the functional changes in vascular reactivity in diabetic rats.     

Feeding and drinking behaviour following angiotensin converting enzyme blockade: role of injectant pH

Angiotensin converting enzyme (ACE) is a circulating dipeptidase which has a broad specificity and is known to metabolise a range of circulating peptides. While a number of circulating peptides are believed to modulate food intake, it is not known if ACE plays a role in the control of feeding behaviour and therefore in this study we have examined the effect of the potent, specific ACE antagonists captopril (SQ 14225) and enalapril (MK421) on food and water intake following food deprivation and 2-deoxyglucose treatment in the rat. One hour captopril (50 mg/kg, IP) pretreatment significantly reduced the food intake of 24 hr food deprived rats. Because captopril solutions have a low pH (2.0), the effect of buffered captopril on food intake following 24 hr food deprivation was also examined. Buffered captopril also significantly reduced the food intake of 24 hr food deprived rats, but not to the same extent as unbuffered captopril. Naloxone pretreatment (1 mg/kg, IP) did not antagonize the effect of captopril on food intake indicating that the anorexic action of captopril was not due to alterations in opiate peptide levels. Buffered captopril did not reduce the food intake of food-replete rats receiving 2-deoxyglucose (300 mg/kg, IP) or alter blood gases or pH. However, an equimolar buffered dose of the structurally different ACE inhibitor enalapril failed to significantly alter food deprivation-induced food intake, suggesting that this action of captopril in reducing food intake was unrelated to ACE blockade.(ABSTRACT TRUNCATED AT 250 WORDS)     

ACE inhibition restores the vasodilator potency of the endothelium-derived relaxing factor, L-S-nitrosocysteine, in conscious Spontaneously Hypertensive rats

OBJECTIVE: The major aim of this study was to determine whether the angiotensin converting enzyme (ACE) inhibitors, captopril or enalapril, restore the diminished vasodilator potency of the endothelium-dependent agonist, acetylcholine (ACh), and the endothelium-derived relaxing factor (EDRF), L-S-nitrosocysteine (L-SNC), in conscious Spontaneously Hypertensive (SH) rats. METHODS: The hemodynamic responses elicited by i.v. injections of ACh, L-SNC, and nitric oxide donors such as MAHMA NONOate, were determined in SH rats treated for 7 days with captopril, enalapril, or the direct vasodilator hydralazine. The effects of captopril, enalapril or hydralazine on oxidant stress levels in blood serum and aorta of WKY and SH rats were also determined. RESULTS: Captopril, enalapril and hydralazine elicited equivalent falls in mean arterial pressure and systemic vascular resistances in SH rats. ACh- and L-SNC-induced vasodilation were increased in captopril- or enalapril-treated SH rats such that the responses were equal to those in normotensive Wistar Kyoto rats. The attenuated responses of ACh and L-SNC in SH rats were not improved by hydralazine. The vasodilator effects of MAHMA NONOate, which were substantially augmented in SH rats, were not affected by captopril, enalapril or hydralazine. The levels of oxidant stress were markedly reduced in captopril- or enalapril-treated but not hydralazine-treated SH rats. CONCLUSIONS: The finding that the ACE inhibitors improved the vasodilator potencies of L-SNC and the EDRF released by ACh in SH rats, suggests that the diminished vasodilator potency of these compounds was due to augmented ACE activity, which increased oxidant stress levels. This study provides the first evidence to support the concept that ACE inhibition lowers arterial pressure in SH rats, at least in part, by restoring the vasodilator potency of endothelium-derived L-SNC.     

Impairment of endothelium-dependent relaxation of rat aortas by homocysteine thiolactone and attenuation by captopril

To explore the effects of angiotensin-converting enzyme (ACE) inhibitors on endothelial dysfunction induced by homocysteine thiolactone (HTL). Both endothelium-dependent relaxation and nondependent relaxation of thoracic aortic rings in rats induced by acetylcholine (Ach) or sodium nitroprusside (SNP) and biochemical parameters including malondialdehyde (MDA) and nitric oxide (NO) were measured in rat isolated aorta. Exposure of aortic rings to HTL (3 to 30 mM) for 90 minutes made a significant inhibition of endothelium-dependent relaxation induced by Ach, decreased contents of NO, and increased MDA concentration in aortic tissue. After incubation of aortic rings with captopril (0.003 to 0.03 mM) attenuated the inhibition of endothelium-dependent relaxation (EDR) and significantly resisted the decrease of NO content and elevation of MDA concentration caused by HTL (30 mmol/L) in aortic tissues, a similarly protective effect was observed when the aortic rings were incubated with both N-acetylcysteine (0.05 mM). Treatment with enalaprilat (0.003 to 0.01 mM) made no significant difference with the HTL (30 mM) group regarding EDR, but enalaprilat (0.03 mM) and losartan (0.03 mM) could partly restore the EDR in response to HTL (30 mM). Captopril was more effective than enalaprilat and losartan in attenuation of the inhibition of on acetylcholine-stimulated aortic relaxation by HTL in the same concentration. Moreover, superoxide dismutase (SOD, 200 U/mL), which is a scavenger of superoxide anions, apocynin (0.03 mM), which is an inhibitor of NADPH oxidase, and l-Arginine (3 mmol/L), a precursor of nitric oxide (NO), could reduce HTL (30 mM)-induced inhibition of EDR. After pretreatment with not only the NO synthase inhibitor Nomega-nitro-l-arginine methyl ester (L-NAME, 0.01 mM) but also the free sulfhydryl group blocking agent p-hydroxymercurybenzoate (PHMB, 0.05 mM) could abolish the protection of captopril and N-acetylcysteine, respectively. These results suggest that mechanisms of endothelial dysfunction induced by HTL may include the decrease of NO and the generation of oxygen free radicals and that captopril can restore the inhibition of EDR induced by HTL in isolated rat aorta, which may be related to scavenging oxygen free radicals and may be sulfhydryl-dependent.     

Pretreatment with captopril improves myocardial recovery after cardioplegic arrest.

Among the interventions designed to limit postischemic oxidative injury, those that enhance the myocardial content of thiol groups are attractive because thiols are powerful antioxidant. Indeed, part of the protection afforded by the angiotensin-converting enzyme (ACE) inhibitor captopril in regional myocardial ischemia is attributed to its thiol group. This study assesses the effects of captopril in a surgically relevant model of global ischemic arrest. Thirty rats were implanted subcutaneously (s.c.) with osmotic pumps that allowed continuous delivery of captopril (total dose 75 mg), enalapril (a nonthiol-containing ACE inhibitor, total dose 7.5 mg) or saline in 48 h. Drug concentrations were equipotent in their effect on angiotensin I (ANGI) pressor response. Hearts were then excised, perfused under isovolumic conditions, and subjected to 90-min cardioplegic arrest at 30 degrees C followed by 1-h reperfusion. Pre- and postischemic coronary flows were significantly higher to a similar extent in the two drug-pretreated groups than in controls. However, captopril-pretreated hearts had the best recovery of contractility (dP/dtmax; 3,590 +/- 74 versus 2915 +/- 64 mm Hg s-1 in the enalapril group, p less than 0.001), and diastolic pressure (13.7 +/- 0.9 mm Hg vs. 20.0 +/- 1.6 mm Hg in the enalapril group, p less than 0.05). We conclude that pretreatment with ACE inhibitors improves myocardial recovery after cardioplegic arrest and that captopril is more effective than enalapril. The additional protection afforded by captopril was not flow mediated, suggesting that the cardioprotective effects of this drug not only involve an ACE inhibition-dependent coronary vasodilation but could be related to a thiol-dependent limitation of oxidative injury.     

Protective effect of enalapril on vascular reactivity of the rat aorta

Cardiovascular complications are the major cause of morbidity and mortality in patients with diabetes mellitus (DM). Strategies that interrupt the renin-angiotensin system have been shown to reduce the ensuing threatening risk factors. The present study was carried out to investigate the effect of subchronic administration of enalapril on the aortic reactivity of streptozotocin (STZ)-diabetic rats. For this purpose, STZ-diabetic rats received enalapril (10 and 20 mg/kg ip) daily for 2 months. Contractile responses to phenylephrine (PE) and relaxation responses to acetylcholine (Ach) and isosorbide dinitrate (ISD) were obtained from aortic rings. Concentration-response curves from enalapril-treated diabetic (ED) rats to PE were attenuated as compared to vehicle-treated diabetics (VD), especially at a dose of 20 mg/kg for enalapril. In addition, endothelium-dependent relaxation responses induced by Ach was significantly higher in ED rats as compared to diabetic ones. The endothelium-independent relaxation responses for ISD were also found not to be significantly different among the groups. Therefore, subchronic treatment of diabetic rats with enalapril in a dose-dependent manner could prevent the functional changes in vascular reactivity in diabetic rats.     

卡托普利对大鼠血管内皮功能损伤的保护作用

目的探讨卡托普利对烟碱所致大鼠血管内皮功能损伤的影响及可能机制。方法将30只大鼠分为3组，即正常对照组、烟碱损伤组（2mg／kg，腹腔注射）、卡托普利保护组（烟碱2mg／kg，腹腔注射＋卡托普利3mg／kg，静脉注射），4周后检测各组肠系膜动脉环内皮依赖性舒张（EDR）反应及主动脉一氧化氮（NO）含量，一氧化氮合成酶（NOS）和超氧化物歧化酶（SOD）活性变化。结果烟碱损伤组肠系膜动脉环EDR明显降低，并伴随主动脉NO含量及NOS，SOD活性的下降；卡托普利保护组血管EDR得到了明显改善，并且抑制了烟碱诱导的主动脉NO含量及NOS，SOD活性的下降。结论卡托普利对烟碱所致血管内皮功能损伤有明显保护作用，该作用与其清除氧自由基、促进内皮细胞合成、释放NO有关。     

Pharmacological studies on (4S)-1-methyl-3-[(2S)-2-[N-((1S)-1-ethoxycarbonyl-3-phenylpropyl)amino] propionyl]-2-oxo-imidazolidine-4-carboxylic acid hydrochloride (TA-6366), a new ACE inhibitor: I. ACE inhibitory and anti-hypertensive activities

TA-6366 and its active metabolite 6366A inhibited swine renal angiotensin converting enzyme (ACE) activity with IC50s of 9900 and 2.6 nM, respectively. TA-6366 (0.05-0.5 mg/kg, p.o.) inhibited the angiotensin I (AT-I)-induced pressor response in rats. 6366A augmented bradykinin (BK)-induced contraction of guinea pig ileum more potently than captopril. However, when the augmentation on BK-induced hypotension in rats was used as an indicator, TA-6366 was less active than captopril. TA-6366 increased plasma renin activity and plasma AT-I concentration. Oral administration of TA-6366 lowered the blood pressure in two-kidney one-clip renal hypertensive rats at 0.5 to 2 mg/kg and in spontaneously hypertensive rats (SHRs) at 2 to 10 mg/kg. The antihypertensive effect of TA-6366 was approximately 5 times more potent than that of captopril and almost as potent as that of enalapril. In SHRs, the antihypertensive action of TA-6366 was intensified in potency when administered repeatedly. The duration of action was longer than those of captopril and enalapril. However, TA-6366 had no substantial effect on the blood pressure in DOCA/saline hypertensive rats. These results indicate that TA-6366 is a potent and long lasting antihypertensive agent and that its antihypertensive action is attributable to the inhibition of ACE.     

EFFECTS OF CHRONIC CONVERTING ENZYME INHIBITION ON THE VASCULAR RENIN-ANGIOTENSIN SYSTEM

1. The effects of chronic oral administration of inhibitors of angiotensin converting enzyme (ACE) on the vascular renin-angiotensin system were studied. 2. Male Sprague-Dawley rats were treated orally with five ACE inhibitors, captopril, enalapril, ramipril, cilazapril and CS-622 (10 mg/kg per day), for periods of 1-2 weeks. Their mesenteric arteries were then isolated and perfused in vitro with Krebs'-Ringer solution, and the angiotensin II (AII) released into the perfusate was measured under unstimulated and isoproterenol-stimulated conditions. The vascular renin activity was also determined after treatments with ACE inhibitors. 3. Treatment with captopril for 1 week suppressed the isoproterenol-stimulated increase in AII release, but had little effect on the baseline release. Oral treatment with captopril for 2 weeks or with other ACE inhibitors for 1 week markedly inhibited both the unstimulated and stimulated release of AII from the mesenteric vasculature. 4. Both the vascular renin activity and the plasma renin activity increased on captopril treatment, but their changes with time were different. 5. These results indicate that virtually complete inhibition of the vascular renin-angiotensin system can be achieved after prolonged treatment with ACE inhibitors, and suggest that the chronic antihypertensive action of ACE inhibitors is not solely due to inhibition of the plasma renin-angiotensin system.     

The protective effect of erdosteine against cyclosporine A-induced cardiotoxicity in rats

Cyclosporine A (CsA) is a frequently used immunosuppressive agent in transplant medicine to prevent rejection and in the treatment of autoimmune diseases. However, CsA generates reactive oxygen species, which causes nephrotoxicity, hepatotoxicity and cardiotoxicity. The use of antioxidants reduces the adverse effects of CsA. The aim of this study is to determine the protective effects of erdosteine on CsA-induced heart injury through tissue oxidant/antioxidant parameters and light microscopic evaluation in rats. CsA cardiotoxicity was induced by administrating an oral dose of 15mg/kg CsA daily for 21 days. The rats were divided into four groups: control group (n=4), CsA administrated group (15mg/kg, n=5), CsA+erdosteine administrated group (10mg/kg day orally erdosteine, n=4) and only erdosteine administrated group (10mg/kg day orally n=5). CsA treated rats showed increase in the number of infiltrated cells and disorganization of myocardial fibers with interstitial fibrosis. The number of infiltrated cells, disorganization of myocardial fibers and interstitial fibrosis was diminished in the hearts of CsA-treated rats given erdosteine. The malondialdehyde, the protein carbonyl content and nitric oxide levels were increased in the cyclosporine A group in comparison with the control and CsA plus erdosteine groups. The activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) were higher in CsA plus erdosteine group than CsA group. However, the CAT, GSH-Px and SOD activities were significantly lower in CsA group than in control group and erdosteine group. These results suggest that erdosteine has protective effect against CsA-induced cardiotoxicity.