Chevillard C, Jouquey S, Bree F, Mathieu M N, Stepniewski J P, Tillement J P, Hamon G, Corvol P
INSERM U300, Montpellier, France.
J Cardiovasc Pharmacol. 1994;23 Suppl 4:S11-5.
The effects of 14-day trandolapril or enalapril treatment of spontaneously hypertensive rats (SHRs) were studied on blood pressure and angiotensin-converting enzyme (ACE) activity measured ex vivo in various organs. Both ACE inhibitors caused dose-dependent decreases in blood pressure and ACE activity, trandolapril being 30- and 400- to 1,000-fold more active than enalapril on blood pressure and ACE activity, respectively. However, comparison of ACE inhibitory activities of the diacid forms of trandolapril and enalapril, i.e., trandolaprilat and enalaprilat, measured in vitro on various tissues, showed that trandolaprilat was only three- to fivefold more active than enalaprilat. To understand the reasons for such discrepancies between ex vivo effects of ACE inhibitors and in vitro actions of their diacid metabolites, we measured the lipophilicities of the compounds and investigated the possibility that trandolapril could display an ACE inhibitory effect by itself. Trandolaprilat was found to be far more lipophilic than enalaprilat, as shown by reverse-phase high-performance liquid chromatography studies performed at pH 7.4 (log kw7.4 = 1.487 vs. 0.108). In addition, trandolapril was practically as active in vitro as its diacid metabolite (IC50 = 2.5 vs. 1.35 nM) in inhibiting ACE activity in the aorta, whereas enalapril was practically devoid of any effect (IC50 = 240 nM). Measurements of relative affinities of inhibitors or metabolites for purified human renal ACE showed that trandolapril displayed about 20% of the affinity of its diacid metabolite (IC50 = 15 vs. 3.2 nM); enalaprilat affinity (34 nM) was within the same range as those of trandolapril and trandolaprilat, whereas enalapril displayed a very low affinity for the purified enzyme (IC50 = 50 microM).(ABSTRACT TRUNCATED AT 250 WORDS)
研究了14天曲坦洛普利或依那普利治疗自发性高血压大鼠（SHR）对血压及离体测量的各器官血管紧张素转换酶（ACE）活性的影响。两种ACE抑制剂均引起血压和ACE活性呈剂量依赖性下降，曲坦洛普利在降低血压和ACE活性方面分别比依那普利强30倍以及400至1000倍。然而，体外测量曲坦洛普利和依那普利二酸形式（即曲坦洛普利拉和依那普利拉）对各种组织的ACE抑制活性，结果显示曲坦洛普利拉仅比依那普利拉活性高3至5倍。为了解ACE抑制剂的离体效应与其二酸代谢产物的体外作用之间存在这种差异的原因，我们测量了这些化合物的亲脂性，并研究了曲坦洛普利自身是否可能发挥ACE抑制作用。通过在pH 7.4条件下进行的反相高效液相色谱研究表明，曲坦洛普利拉的亲脂性远高于依那普利拉（log kw7.4 = 1.487对0.108）。此外，曲坦洛普利在体外抑制主动脉中ACE活性的作用与其二酸代谢产物几乎相同（IC50 = 2.5对1.35 nM），而依那普利几乎没有任何作用（IC50 = 240 nM）。对抑制剂或代谢产物与纯化的人肾ACE的相对亲和力测量表明，曲坦洛普利表现出其二酸代谢产物约20%的亲和力（IC50 = 15对3.2 nM）；依那普利拉的亲和力（34 nM）与曲坦洛普利和曲坦洛普利拉在同一范围内，而依那普利对纯化酶的亲和力非常低（IC50 = 50 microM）。（摘要截短于250字）
