In vivo effects of endothelin A- and B-receptor antagonists in guinea pigs
Nagase, T.; Fukuchi, Y.; Matsui, H.; Aoki, T.; Matsuse, T.; Orimo, H.
American Journal of Physiology 268(5 Pt 1): L846-L850
1995
ISSN/ISBN: 0002-9513 PMID: 7762687 Document Number: 440832
Endothelin (ET)-1, a novel 21-amino acid constrictor peptide, has been recently reported to have a potential pathophysiological role in asthma. We hypothesized that ET-1 might affect guinea pig lung via different ET receptor subtypes, i.e., ET-A and ET-B, in vivo. To test this hypothesis, we investigated the effects of ET-1 on airways in anesthetized, open-chest, mechanically ventilated (frequency (f) = 1 Hz; tidal volume (V-T) = 9 ml/kg; positive end-expiratory pressure (PEEP) = 4 cmH-2O) guinea pigs in the absence or the presence of ET-A and ET-B selective antagonists, i.e., BQ-123 and BQ-788, respectively. We affixed alveolar capsules to the lungs to measure alveolar pressure and calculated the elastance of lung (E-L) and the resistance of lung (R-L), tissue (R-ii), and airway (R-aw) under control conditions and after intravenous administration of ET-1 (10-8 mol/kg). ET-1 induced a concentration-dependent increase in R-L, R-ti, R-aw, and E-L. BQ-123 (2 mg/kg) partially blocks DELTA-R-L and DELTA-R-aw during ET-1 induced constriction, while DELTA-R-ti and DELTA-E-L were not significantly affected. BQ-788 (2 mg/kg) significantly inhibited DELTA-R-L, DELTA-R-ti, DELTA-R-aw, and DELTA-E-L during ET-1-induced constriction. The combination of BQ-123 and BQ-788 completely ablated the response to ET-1. These data suggest that both ET receptor subtypes, i.e., ET-A and ET-B, may have physiological roles in guinea pig airways in response to ET-1, a potential mediator of asthma.