Analysis of responses to bradykinin and influence of HOE 140 in the isolated perfused rat lung.

The inhibitory effects of HOE 140, a novel bradykinin B2 receptor antagonist, on pulmonary vascular and airway responses to bradykinin (BK) were investigated under conditions of controlled pulmonary blood flow and ventilation and constant left atrial pressure in the isolated blood-perfused rat lung. Under baseline conditions, BK produced dose-related increases in pulmonary arterial perfusion pressure without changing airway pressure. However, when pulmonary arterial pressure was raised to a high steady level, increases in pulmonary arterial pressure in response to BK were enhanced and BK then produced dose-related increases in airway pressure. Responses to BK were reproducible with respect to time and were not different when the inspired fraction of O2 was 0.21 or 0.95 and HOE 140 was 0.8 nM/ml (50 micrograms/kg) and decreased both pulmonary vascular and airway responses to the peptide. HOE 140 had no significant effect on pulmonary vascular responses to angiotensin II, serotonin, nitric oxide, sodium nitroprusside, albuterol, or pinacidil. Additionally, in these experiments, HOE 140 had no effect on the pulmonary arterial pressor response to ventilatory hypoxia. These results suggest BK has significant vasoconstrictor and bronchoconstrictor effects that are mediated by B2 receptors and are dependent on the baseline level of tone in the airways and in the pulmonary vascular bed. The present results suggest that HOE 140 is a highly selective, BK B2 receptor antagonist in the pulmonary vascular bed of the rat. These data also suggest that HOE 140 may be a useful probe for studying the role of BK in the pulmonary vascular bed in physiological and pathophysiological conditions.