EFFECT OF HOE-140 ON BRADYKININ-INDUCED BRONCHOCONSTRICTION IN ANESTHETIZED GUINEA-PIGS

We have investigated the efficacy of the novel, highly potent, and sta ble B2 bradykinin (BK) antagonist Hoe 140 against BK-induced bronchoco nstriction in guinea pigs via whole body plethysmography and compared different routes of administration. Our results clearly demonstrate th at Hoe 140 is highly potent at inhibiting bronchoconstriction induced by either intravenous (iv.) or inhaled BK. Intravenous BK was strongly inhibited by iv. Hoe 140 (ID50 13.4 pmol/kg), and less by aerosolized Hoe 140 (ID50 1.34 nmol/kg). Aerosolized BK (235 nmol/kg) was strongl y 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 broncho constrictor effect of aerosolized BK. The equieffective i.v. dose of H oe 140, however, as about 100-fold higher. From the discrepancy in eff icacy of Hoe 140 against iv. and aerosolized BK, it was concluded that iv. BK has no direct effect on the lung, in contrast to inhaled BK. M oreover, the high potency of Hoe 140 in the guinea pig lung does not c onfirm the hypothesis of a B3 BK receptor. Based on its high potency a nd good tolerability, Hoe 140 is appropriate to evaluate the role of B K in human airway diseases.