Influence of respiratory tract viral infection on endothelin-1-induced potentiation of cholinergic nerve-mediated contraction in mouse trachea.
1. This study examined the influence of respiratory tract infection with influenza A/PR-8/34 virus on endothelin receptor-mediated modulation of contraction induced by stimulation of cholinergic nerves in mouse isolated trachea. 2. The ETB receptor-selective agonist, sarafotoxin S6c (30 nM) induced large transient contractions (118 +/- 5% Cmax, n = 13; where Cmax is the contraction induced by 10 microM carbachol) of isolated tracheal segments from control mice. The peak contractile response to 30 nM sarafotoxin S6c was significantly lower in preparations from virus-inoculated mice at day 2 (57 +/- 8% Cmax, n = 3, P < 0.05) and 4 post-inoculation (90 +/- 8% Cmax, n = 9, P < 0.05), consistent with virus-induced attentuation of the ETB receptor-effector system linked to airway smooth muscle contraction. The mean peak contraction to 30 nM sarafotoxin S6c of preparations from virus-inoculated mice at day 8 post-inoculation (94 +/- 17% Cmax, n = 4) was not significantly different from that of control. 3. Electrical field stimulation (EFS; 90 V, 0.5 ms duration, 10 s train, 0.1-30 Hz) of preparations from control and virus-inoculated mice, caused contractions that were abolished by 0.1 microM atropine or 3 microM tetrodotoxin, indicating that these responses were mediated by neuronally released acetylcholine. Sarafotoxin S6c markedly potentiated contractions induced by a standard stimulus (0.3 Hz, every 3 min) in tracheal segments from control and virus-inoculated mice. In tracheal tissue from control mice, 30 nM sarafotoxin S6c significantly increased a standard EFS-induced contraction of 24 +/- 4% Cmax by a further 24 +/- 3% Cmax (i.e. 2 fold increase, n = 11). Sarafotoxin S6c (30 nM) also markedly potentiated standard EFS-induced contractions in preparations from virus-inoculated mice at day 2 (17 +/- 2% Cmax, n = 3), day 4 (17 +/- 5% Cmax, n = 9) and day 8 (26 +/- 5% Cmax, n = 4) post-inoculation. The level of potentiation of EFS-induced contractions in preparations from virus-inoculated mice was similar to that in tissue from control mice at days, 2, 4 and 8 post-inoculation. In contrast, sarafotoxin S6c (30 nM) did not enhance contractile responses of tracheal segments from control and virus-inoculated mice to exogenously applied acetylcholine (n = 3). 4. Endothelin-1 (1 nM) caused similar potentiations of standard EFS-induced contractions in tracheal segments from control (13 +/- 2% Cmax, n = 23) and virus-inoculated mice at day 2 (13 +/- 1% Cmax, n = 5), day 4 (16 +/- 5% Cmax, n = 6), and day 8 (13 +/- 3% Cmax, n = 8) post-inoculation. In contrast, 1 nM endothelin-1 did not enhance contractile responses of tracheal segments from control and virus-inoculated mice to exogenously applied acetylcholine (n = 4). Neither the ETA receptor-selective antagonist, BQ-123 (3 microM) nor the ETB receptor-selective antagonist, BQ-788 (1 microM) alone had any significant inhibitory effect on endothelin-1-induced potentiations of tracheal segments from control or virus-inoculated mice at days 2, 4 and 8 post-inoculation. However, simultaneous pre-incubation with BQ-123 (3 microM) and BQ-788 (1 microM) prevented endothelin-1-evoked potentiations, indicative of a role for both ETA and ETB receptors in this system. 5. These data clearly demonstrate that respiratory tract viral infection attenuated the function of the postjunctional ETB receptor-effector system linked directly to airway smooth muscle contraction. However, the function of prejunctional ETA and ETB receptor-effector systems linked to augmentation of cholinergic nerve-mediated airway smooth muscle contraction remained unaffected during respiratory tract viral infection in mice.
Carr
M J
MJ
Department of Pharmacology, University of Western Australia, Nedlands.
Goldie
R G
RG
Henry
P J
PJ
D000818:Animals; D019332:Endothelin-1 / Q000502:physiology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009976:Orthomyxoviridae Infections / Q000378:metabolism* / Q000503:physiopathology; D011950:Receptors, Cholinergic / Q000502:physiology*; D017466:Receptors, Endothelin / Q000187:drug effects / Q000502:physiology; D012141:Respiratory Tract Infections / Q000378:metabolism* / Q000503:physiopathology; D014132:Trachea / Q000187:drug effects / Q000503:physiopathology*; D014757:Viper Venoms / Q000494:pharmacology
D019332:Endothelin-1; D011950:Receptors, Cholinergic; D017466:Receptors, Endothelin; D014757:Viper Venoms; C057354:sarafotoxins s6