Time course of changes in ET_B receptor density and function in tracheal airway smooth muscle during respiratory tract viral infection in mice

摘要

1 In the current study, the density and function of ET_A and ET_B receptors in mouse tracheal airway smooth muscle were determined over the time course of respiratory tract infection with influenza A/PR-8/34 virus. 2 Quantitative autoradiographic studies using [~(125)I]-endothelin-1 revealed that the tracheal airway smooth muscle from control mice contained ET_A and ET_B sites in the ratio of 49%:51% (±2%, n = 29 mice). Respiratory tract viral infection was associated with increases in the density of ET_A sites and decreases in the density of ET_B sites at days 1, 2 and 4 post-inoculation which were reversible by day 19. For example, at day 4 post-inoculation, a time when the manifestations of viral infection were at or near their peak, the ratio of ET_A:ET_B sites was 72%:28% (±4%, n = 6 mice, P<0.05). In contrast, at day 19 post-inoculation, by which time viral infection had essentially resolved, the ratio of ET_A:ET_B sites was similar to control (51%:49% (±3%), n = 6 mice). 3 Endothelin-1 was a potent spasmogen in isolated tracheal airway smooth muscle preparations from control mice (ED_(70) = concentration producing 70% of contraction induced by 10 μM carbachol = 6.3 nM (95% confidence limits, 4.0-10; n = 6 mice)). Neither the ET_A receptor-selective antagonist, BQ-123 (3 μM), nor the ET_B receptor-selective antagonist, BQ-788 (1 μM) alone had any significant inhibitory effect on endothelin-1-induced contractions of mouse isolated tracheal smooth muscle. However, simultaneous treatment with BQ-123 (3 μM) and BQ-788 (1 μM) resulted in a 10 fold rightward shift in the concentration-effect curve to endothelin-1 (ED_(70) = 60 nM, (44-90; n = 6 mice, P < 0.05)), indicating that contraction was mediated via both ET_A and ET_B receptors.