Interaction between neutral endopeptidase and angiotensin converting enzyme inhibition in rats with myocardial infarction: Effects on cardiac hypertrophy and angiotensin and bradykinin peptide levels

作     者：Duncan, AM James, GM Anastasopoulos, F Kladis, A Briscoe, TA Campbell, DJ 

作者机构：St Vincents Inst Med Res Fitzroy Vic 3065 Australia 

出 版 物：《JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS》 (药理学与实验治疗学杂志)

年 卷 期：1999年第289卷第1期

页      面：295-303页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 100706[医学-药理学] 100602[医学-中西医结合临床] 10[医学] 

主　　题：血管紧张素Ⅱ/代谢 血管紧张素转换酶抑制药/药理学 体重/药物作用 缓激肽/代谢 心脏扩大/并发症 心脏扩大/病理学 环GMP/尿 药物协同作用 吲哚类/药理学 心肌梗死/并发症 心肌梗死/代谢 心肌梗死/病理学 心肌梗死/病理生理学 脑啡肽酶/拮抗剂和抑制剂 肽基二肽酶A/血液 培哚普利 钾/尿 蛋白酶抑制药/药理学 放射免疫测定 大鼠 Sprague-Dawley 肾素/血液 钠/尿 硫甲基氧代苯丙甘氨酸/类似物和衍生物 硫甲基氧代苯丙甘氨酸/药理学 动物 男(雄)性 大鼠 

摘      要：Combined inhibition of neutral endopeptidase 24.11 (NEP) and angiotensin converting enzyme (ACE) is a candidate therapy for hypertension and cardiac failure. Given that NEP and ACE metabolize angiotensin (Ang) and bradykinin (BK) peptides, we investigated the effects of NEP inhibition and combined NEP and ACE inhibition on Ang and BK levels in rats with myocardial infarction. We administered the NEP inhibitor ecadotril (0, 0.1, 1, 10, and 100 mg/kg/day), either alone or together with the ACE inhibitor perindopril (0.2 mg/kg/day) by 12-hourly gavage from day 2 to 28 after infarction. Ecadotril increased urine cyclic GMP and BK-(1-9) excretion. Perindopril potentiated the effect of ecadotril on urine cyclic GMP excretion. Neither perindopril nor ecadotril reduced cardiac hypertrophy when administered separately, whereas the combination of perindopril and 10 or 100 mg/kg/day ecadotril reduced heart weight/body weight ratio by 10%. Administration of ecadotril to perindopril-treated rats decreased plasma Ang-(1-7) levels, increased cardiac BK(1-9) levels, and increased Ang II levels in plasma, kidney, aorta, and lung. These data demonstrate interactions between the effects of NEP and ACE inhibition on remodeling of the infarcted heart and on Ang and BK peptide levels. Whereas increased cardiac BK-(1-9) levels may contribute to the reduction of cardiac hypertrophy, the reduction in plasma Ang-(1-7) levels and increase in Ang II levels in plasma and tissues may compromise the therapeutic effects of combined NEP/ACE inhibition.