1 The current study investigated the effects of respiratory tract viral infection on the density of ETA and ETB receptors in murine tracheal smooth muscle and on the contractile response to endothelin-1 mediated by these receptors. 2 Quantitative autoradiographic studies using ['251]-endothelin-l revealed that tracheal smooth muscle from control mice contained ETA and ETB receptors in the ratio of 42%:58% ( + 4%, n = 10 mice), respectively. In contrast, tracheal smooth muscle obtained from mice 2 days post-inoculation with Influenza A/PR-8/34 virus contained 23 ± 2% fewer receptors for ['25I]-endothelin-l (n = 10, P<0.01).This reflected a selective reduction in ETB receptor density and a change in the ratio of ETA and ETB receptors to 77% :23% ( ± 5%, n = 10 mice), respectively. 3 The ETB receptor-selective agonist, sarafotoxin S6c, was a potent spasmogen of murine isolated tracheal smooth muscle and the EC50 for contraction was similar in preparations from control (3.6 nM [95% confidence limits, 2.7-4.8 nM], n = 16 preparations from 8 mice) and virus-inoculated mice (3.0 nM [2.4-3.7 nM], n = 16 preparations from 8 mice). However, the maximum contractions induced by sarafotoxin S6c (100 nM) in the preparations from virus-inoculated mice (37 ± 5% Cm., where 100%Cm., was the response to 10IM carbachol) were significantly smaller than those from control mice (85±4% Cmax, P<0.01). 4 Contractions induced by endothelin-1 in tracheal smooth muscle preparations obtained from virusinoculated mice (EC" for contraction, 6.5 nM [95% confidence limits, 2.7-16 nM]; maximum contraction, 112 ± 5% Cm.; n = 4) were similar to those induced by endothelin-1 in control preparations (ECm 9.3 nM (4.2-21); maximum contraction, 110 ± 3% C,,,.a; n = 4). Endothelin-1-induced contractions in control preparations were only marginally inhibited by the ETA receptor-selective antagonist BQ-123 (in the presence of 3 jLM BQ-123; EC50 for contraction, 5.9 nM [4.1-8.5]; maximum contraction, 82 ± 4% Cx,,,; n = 4). In contrast, 3 tiM BQ-123 caused a 50 fold rightward shift (17-160, n =4) of the concentration-effect curve to endothlin-1 in preparations obtained from virus-inoculated mice (measured at the 30% C=,, level of contraction). 5 Tracheal smooth muscle preparations exposed to 100 nM sarafotoxin S6c for 30 min (followed by a 30 min washout period) did not contract to subsequently administered sarafotoxin S6c (1-100 nM; n = 8), but contracted normally in response to endothelin-1 (EC50 6.5 nM (2.3-18); maximum contraction, 109 ± 2% Cm,,; n = 4). Endothelin-l-induced contractions in these ETB receptor desensitized preparations were markedly inhibited by 3 ILM BQ-123, irrespective of whether the preparations were obtained from control (63 fold shift (10-400) at the 30% Cma. level of contraction, n = 4) or virusinoculated mice (46 fold shift (18-120), n = 4). 6 In summary, tracheal smooth muscle obtained from mice infected with a respiratory tract virus, Influenza A/PR-8/34 had a reduced density of ETB receptors and an attenuated ETB receptor-med...