Véniant M, Clozel J P, Fischli W
Pharmaceutical Research Department, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
J Hypertens. 1992 Feb;10(2):155-60. doi: 10.1097/00004872-199202000-00008.
The goal of the present study was to show that, in contrast to an angiotensin converting enzyme (ACE) inhibitor, Ro 42-5892, a new renin inhibitor, can block the renin-angiotensin system without potentiating skin reactions induced by bradykinin.
Potentiation of skin reaction to i.d. injections of bradykinin and histamine was evaluated in guinea pigs in the presence and absence of the drug (placebo, Ro 42-5892 or cilazapril). The elimination rate of radioactive bradykinin in blood was measured in other groups of guinea pigs treated with the same drugs. Maximal effective doses of each drug were used.
Measurements of erythema area induced by bradykinin and histamine injection were performed using a digital planimeter. Radioactive bradykinin was measured in blood by high-performance liquid chromatography and followed over 40 min.
The ACE inhibitor cilazapril increased the area of erythema induced by bradykinin but not that induced by histamine. In contrast, Ro 42-5892 did not potentiate the effect of bradykinin. In addition, cilazapril did not change the elimination rate of i.v. radioactive bradykinin in blood.
These results suggest that potentiation of bradykinin-induced skin reaction by cilazapril is due to a tissular (and not systemic) inhibition of ACE and does not occur with Ro 42-5892. Thus, side effects such as rash, angioneurotic edema or cough, which have been attributed to bradykinin accumulation by ACE inhibitors, may not occur with the use of specific renin inhibitors such as Ro 42-5892.
本研究的目的是表明，与血管紧张素转换酶（ACE）抑制剂不同，新型肾素抑制剂Ro 42-5892可阻断肾素-血管紧张素系统，而不会增强缓激肽诱导的皮肤反应。
在有或没有药物（安慰剂、Ro 42-5892或西拉普利）存在的情况下，评估豚鼠对皮下注射缓激肽和组胺的皮肤反应增强情况。在接受相同药物治疗的其他豚鼠组中测量血液中放射性缓激肽的消除率。使用每种药物的最大有效剂量。
使用数字面积测量仪测量缓激肽和组胺注射诱导的红斑面积。通过高效液相色谱法测量血液中的放射性缓激肽，并跟踪40分钟。
ACE抑制剂西拉普利增加了缓激肽诱导的红斑面积，但没有增加组胺诱导的红斑面积。相比之下，Ro 42-5892没有增强缓激肽的作用。此外，西拉普利没有改变静脉注射放射性缓激肽在血液中的消除率。
这些结果表明，西拉普利增强缓激肽诱导的皮肤反应是由于对ACE的组织（而非全身）抑制，而Ro 42-5892不会出现这种情况。因此，使用特异性肾素抑制剂如Ro 42-5892时，可能不会出现归因于ACE抑制剂导致缓激肽蓄积的皮疹、血管神经性水肿或咳嗽等副作用。
