Mj. Carr et al., TIME-COURSE OF CHANGES IN ET(B) RECEPTOR DENSITY AND FUNCTION IN TRACHEAL AIRWAY SMOOTH-MUSCLE DURING RESPIRATORY-TRACT VIRAL-INFECTION IN MICE, British Journal of Pharmacology, 117(6), 1996, pp. 1222-1228
1 In the current study, the density and function of ET(A) and ET(B) re
ceptors in mouse tracheal airway smooth muscle were determined over th
e time course of respiratory tract infection with influenza A/PR-8/34
virus. 2 Quantitative autoradiographic studies using [I-125]-endotheli
n-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 m
ice). Respiratory tract viral infection was associated with increases
in the density of ET(A) sites and decreases in the density of ET(B) si
tes at days 1, 2 and 4 post-inoculation which were reversible by day 1
9. For example, at day 4 post-inoculation, a time when the manifestati
ons 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 re
solved, the ratio of ET(A):ET(B) sites was similar to control (51%:49%
(+/-3%), n=6 mice). 3 Endothelin-l was a potent spasmogen in isolated
tracheal airway smooth muscle preparations from control mice (ED(70)=
concentration producing 70% of contraction induced by 10 mu M carbacho
l=6.3 nM (95% confidence limits, 4.0-10; n=6 mice)). Neither the ET(A)
receptor-selective antagonist, BQ-123 (3 mu M), nor the ET(B) recepto
r-selective antagonist, BQ-788 (1 mu M) alone had any significant inhi
bitory effect on endothelin-l-induced contractions of mouse isolated t
racheal smooth muscle. However, simultaneous treatment with BQ-123 (3
mu M) and BQ-788 (1 mu M) resulted in a 10 fold rightward shift in the
concentration-effect curve to endothelin-l (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. 4 Endothelin-l evoked similar concentration-de
pendent contractions of tracheal smooth muscle isolated from control a
nd virus-inoculated mice. In the presence of the ET(B) receptor-select
ive-antagonist, BQ-788 (1 mu M), the potency and maximum response to e
ndothelin-l were similar in preparations from control and virus-inocul
ated mice at all time points investigated. However, unlike control res
ponses, endothelin-l-induced contractions in preparations from virus-i
nfected mice were significantly inhibited by the ET(A) receptor-select
ive antagonist, BQ-123. For example, at day 4 post-inoculation, the co
ntractile response to 30 nM endothelin-l, in the presence of BQ-123 (3
mu M), was only 20+/-12% (n=6 mice, P<0.05) of that produced in contr
ol preparations under similar conditions. However, at day 19 post-inoc
ulation, contraction evoked by 30 nM endothelin-l in the presence of B
Q-123 (3 mu M), was similar to that in preparations from control mice.
5 In summary, during the early stages (days 1-8 post-inoculation) of
respiratory tract infection with influenza A/PR-8/34 virus, we observe
d decreases in the density of tracheal airway smooth muscle ET(B) rece
ptors which were reflected in decreases in ET(B) receptor-mediated air
way smooth muscle contraction. In addition, during the same period of
viral infection we observed increases in the density of tracheal airwa
y smooth muscle ET(A) receptors which were not associated with increas
ed function of the ET(A) receptor-effector system linked to contractio
n. Virus-associated modulation of ET(A) and ET(B) receptor density and
function was reversible with recovery from infection.