Daull Philippe, Blouin André, Sirois Pierre, Nantel François, Jeng Arco Y, Battistini Bruno
Laval Hospital Research Center, Quebec Heart & Lung Institute, Laval University, Québec, QC, Canada.
J Cardiovasc Pharmacol. 2004 Nov;44 Suppl 1:S398-401. doi: 10.1097/01.fjc.0000166293.79948.09.
Inhibition of the renin-angiotensin system with an angiotensin-converting enzyme inhibitor (ACEi) is an effective therapy in hypertension. Vasopeptidase inhibition was initially proposed with compounds inhibiting both angiotensin-converting enzyme and neutral endopeptidase (omapatrilat), but clinical trials revealed that reducing angiotensin II while blocking the degradation of vasodilatory peptides was not without concerns. We have previously investigated the combination of an ACEi with an endothelin-converting enzyme inhibitor (ECEi); now we add a neutral endopeptidase inhibitor (NEPi) toward triple vasopeptidase inhibition. Male spontaneously hypertensive rats were surgically implanted with a vascular catheter and treated with an ACEi (benazepril), a NEPi (CGS 24592) and an ECEi (CGS 35066) (continuous intra-arterial infusion at 1 or 5 mg/kg/day x 5 days each). After 15 days, drugs administration was stopped for 3 days. ACEi (1 mg/kg per day) reduced the mean arterial blood pressure by 8.4%. The addition of a NEPi and an ECEi at the same dose did not shown any added benefit. The mean arterial blood pressure came back to baseline upon cessation of treatment. ACEi (5 mg/kg per day) reduced the mean arterial blood pressure by 28%. The mean arterial blood pressure remained attenuated by 21% and 19% with the addition of the NEPi and the ECEi. Again, the mean arterial blood pressure rose back to 148 +/- 4 mmHg following cessation of treatment. Daily biochemical and hematological analysis of plasma did not reveal any signs of toxicity, except for a rapid elevation in K (40%) after 1 day of ACEi. Thus, angiotensin II inhibition plays a primary role in controlling the blood pressure of spontaneously hypertensive whereas additional NEPi and ECEi did not provide further benefits under the present dose combinations. The normalizing effect of the higher dose of ACEi by itself made it impossible to discriminate the role of neutral endopeptidase and endothelin-converting enzyme-modulated peptides and to further define the paradigm of triple vasopeptidase inhibition toward better control of vascular hemodynamics. Additional studies are underway.
使用血管紧张素转换酶抑制剂（ACEi）抑制肾素-血管紧张素系统是治疗高血压的有效方法。最初提出使用抑制血管紧张素转换酶和中性内肽酶的化合物（奥美普利拉）进行血管肽酶抑制，但临床试验表明，在阻断血管舒张肽降解的同时降低血管紧张素II并非毫无问题。我们之前研究了ACEi与内皮素转换酶抑制剂（ECEi）的联合使用；现在我们添加一种中性内肽酶抑制剂（NEPi）以实现三重血管肽酶抑制。雄性自发性高血压大鼠通过手术植入血管导管，并接受ACEi（贝那普利）、NEPi（CGS 24592）和ECEi（CGS 35066）治疗（连续动脉内输注，剂量为1或5mg/kg/天，各持续5天）。15天后，停药3天。ACEi（1mg/kg/天）使平均动脉血压降低了8.4%。添加相同剂量的NEPi和ECEi未显示出任何额外益处。停药后平均动脉血压恢复到基线水平。ACEi（5mg/kg/天）使平均动脉血压降低了28%。添加NEPi和ECEi后，平均动脉血压分别维持在比基线水平低21%和19%的水平。同样，停药后平均动脉血压回升至148±4mmHg。除了在使用ACEi 1天后血钾迅速升高（40%）外，每日对血浆进行的生化和血液学分析未发现任何毒性迹象。因此，抑制血管紧张素II在控制自发性高血压大鼠血压中起主要作用，而在当前剂量组合下，额外添加NEPi和ECEi并未带来进一步益处。较高剂量的ACEi本身的血压正常化作用使得无法区分中性内肽酶和内皮素转换酶调节肽的作用，也无法进一步明确三重血管肽酶抑制在更好控制血管血流动力学方面的模式。更多研究正在进行中。
