Pj. Henry et Rg. Goldie, ET(B) BUT NOT ET(A) RECEPTOR-MEDIATED CONTRACTIONS TO ENDOTHELIN-1 ATTENUATED BY RESPIRATORY-TRACT VIRAL-INFECTION IN MOUSE AIRWAYS, British Journal of Pharmacology, 112(4), 1994, pp. 1188-1194
1 The current study investigated the effects of respiratory tract vira
l infection on the density of ET(A) and ET(B) receptors in murine trac
heal smooth muscle and on the contractile response to endothelin-1 med
iated by these receptors. 2 Quantitative autoradiographic studies usin
g [I-125]-endothelin-1 revealed that tracheal smooth muscle from contr
ol mice contained ET(A) and ET(B) 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 v
irus contained 23 +/- 2% fewer receptors for [I-125]-endothelin-1 (n =
10, P < 0.01). This reflected a selective reduction in ET(B) receptor
density and a change in the ratio of ET(A) and ET(B) receptors to 77%
:23% (+/- 5%, n = 10 mice), respectively. 3 The ET(B) receptor-selecti
ve agonist, sarafotoxin S6c, was a potent spasmogen of murine isolated
tracheal smooth muscle and the EC(50) 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 con
tractions induced by sarafotoxin S6c (100 nM) in the preparations from
virus-inoculated mice (37 +/- 5% C-max, where 100% C-max was the resp
onse to 10 mu M carbachol) were significantly smaller than those from
control mice (85 +/- 4% C-max, P < 0.01). 4 Contractions induced by en
dothelin-1 in tracheal smooth muscle preparations obtained from virus-
inoculated mice (EC(50) for contraction, 6.5 nM [95% confidence limits
, 2.7-16 nM]; maximum contraction, 112 +/- 5% C-max; n = 4) were simil
ar to those induced by endothelin-1 in control preparations (EC(50) 9.
3 nM (4.2-21) maximum contraction, 110 +/- 3% C-max; n = 4). Endotheli
n-1-induced contractions in control preparations were only marginally
inhibited by the ET(A) receptor-selective antagonist BQ-123 (in the pr
esence of 3 mu M BQ-123; EC(50), for contraction, 5.9 nM [4.1-8.5]; ma
ximum contraction, 82 +/- 4% C-max; n = 4). In contrast, 3 mu M 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-inocu
lated mice (measured at the 30% C-max level of contraction).5 Tracheal
smooth muscle preparations exposed to 100 nM sarafotoxin S6c for 30 m
in (followed by a 30 min washout period) did not contract to subsequen
tly administered sarafotoxin S6c (1-100 nM; n = 8), but contracted nor
mally in response to endothelin-1 (ECM(50) 6.5 nM (2.3-18); maximum co
ntraction, 109 +/- 2% C-max; n = 4). Endothelin-1-induced contractions
in these ET(B) receptor desensitized preparations were markedly inhib
ited by 3 mu M BQ-123, irrespective of whether the preparations were o
btained from control (63 fold shift (10-400) at the 30% C-max level of
contraction, n = 4) or virus-inoculated mice (46 fold shift (18-120),
n = 4). 6 In summary, tracheal smooth muscle obtained from mice infec
ted with a respiratory tract virus, Influenza A/PR-8/34 had a reduced
density of ET(B) receptors and an attenuated ET(B) receptor-mediated c
ontractile response to sarafotoxin S6c and endothelin-1. Virus-inocula
tion was also associated with a modest increase in tracheal smooth mus
cle ET(A) receptor density, although no significant change in ET(A) re
ceptor-mediated contractile activity was seen. Thus, virus infection i
n murine airways produced profound alterations in endothelin receptor
density, some of which were associated with changes in receptor-mediat
ed contractile activity.