Wirth K J, Gehring D, Schölkens B A
Hoechst AG, Frankfurt, Germany.
Am Rev Respir Dis. 1993 Sep;148(3):702-6. doi: 10.1164/ajrccm/148.3.702.
We have investigated the efficacy of the novel, highly potent, and stable B2 bradykinin (BK) antagonist Hoe 140 against BK-induced bronchoconstriction in guinea pigs via whole body plethysmography and compared different routes of administration. Our results clearly demonstrate that Hoe 140 is highly potent at inhibiting bronchoconstriction induced by either intravenous (i.v.) or inhaled BK. Intravenous BK was strongly inhibited by i.v. Hoe 140 (ID50 13.4 pmol/kg), and less by aerosolized Hoe 140 (ID50 1.34 nmol/kg). Aerosolized BK (235 nmol/kg) was strongly inhibited by 0.1 nmol/kg of aerosolized Hoe 140 given 30 min before. Hoe 140 is the first BK antagonist to effectively inhibit the bronchoconstrictor effect of aerosolized BK. The equieffective i.v. dose of Hoe 140, however, as about 100-fold higher. From the discrepancy in efficacy of Hoe 140 against i.v. and aerosolized BK, it was concluded that i.v. BK has no direct effect on the lung, in contrast to inhaled BK. Moreover, the high potency of Hoe 140 in the guinea pig lung does not confirm the hypothesis of a B3 BK receptor. Based on its high potency and good tolerability, Hoe 140 is appropriate to evaluate the role of BK in human airway diseases.
我们通过全身体积描记法研究了新型、高效且稳定的B2缓激肽（BK）拮抗剂Hoe 140对豚鼠BK诱导的支气管收缩的疗效，并比较了不同给药途径。我们的结果清楚地表明，Hoe 140在抑制静脉注射（i.v.）或吸入BK诱导的支气管收缩方面具有高效性。静脉注射的BK被静脉注射的Hoe 140强烈抑制（半数抑制剂量[ID50]为13.4 pmol/kg），而雾化的Hoe 140对其抑制作用较弱（ID50为1.34 nmol/kg）。在给药前30分钟给予0.1 nmol/kg的雾化Hoe 140可强烈抑制雾化的BK（235 nmol/kg）。Hoe 140是首个有效抑制雾化BK支气管收缩作用的BK拮抗剂。然而，Hoe 140的等效静脉注射剂量约高100倍。从Hoe 140对静脉注射和雾化BK疗效的差异得出结论，与吸入的BK相反，静脉注射BK对肺无直接作用。此外，Hoe 140在豚鼠肺中的高效性并未证实存在B3 BK受体的假设。基于其高效性和良好的耐受性，Hoe 140适合用于评估BK在人类气道疾病中的作用。
