INFLUENCE OF PARAINFLUENZA-1 RESPIRATORY-TRACT VIRAL-INFECTION ON ENDOTHELIN RECEPTOR-EFFECTOR SYSTEMS IN MOUSE AND RAT TRACHEAL SMOOTH-MUSCLE

1 In this study we have compared the effects of parainfluenza-l respir atory tract viral infection on the density and function of ET(A) and E T(B) receptors in rat and mouse tracheal airway smooth muscle. 2 The b ronchoconstrictor effect of inhaled methacholine was significantly enh anced in virus-infected rats, at both 4 and 12 days post-inoculation. That is, the concentration of methacholine causing an increase in resi stance of 100% (PC100 methacholine) was significantly lower in virus-i nfected animals at both 4 and 12 days post-inoculation (n=6-8; P<0.05) . 3 Total specific binding of [I-125]-endothelin-1 and the relative pr oportions of ET(A) and ET(B) binding sites for [I-125]-endothelin-1 we re assessed in tracheal airway smooth muscle in parainfluenza-1-infect ed rats and mice at days 2, 4 and 12 post-inoculation using the ligand s BQ-123 (1 mu M; ET(A) receptor-selective) and sarafotoxin S6c (100 n M; ET(B) receptor-selective). Total specific binding in mice was signi ficantly reduced at day 2 post-inoculation (n=5; P<0.05) but not at da ys 4 and 12 post-inoculation (n=5). In control mice, the proportions o f ET(A) and ET(B) binding sites were 53%:47% at day 2 and 43%:57% at d ay 4 and these were significantly altered by parainfluenza-l infection such that, the ratios were 81%:19% at day 2 and 89%:11% at day 4 (P<0 .05). By day 12 post-inoculation, the proportion of ET(A) and ET(B) bi nding sites in tracheal smooth muscle from mice infected with parainfl uenza-l was not significantly different from control. In rat tracheal airway smooth muscle, neither total specific binding nor the ET(A) and ET(B) binding site ratio (64%:36%) were significantly altered in viru s-inoculated rats at days 2, 4 or 12 post-inoculation (n=5). 4 Parainf luenza-l infection in mice had no effect on the sensitivity or maximal contractile effect of endothelin-l in tracheal smooth muscle at days 2, 4 or 12 post-inoculation (n=4). In contrast, contraction in respons e to the ET(B) receptor-selective agonist sarafotoxin S6c was attenuat ed by 39% at day 2 and by 93% at day 4 post-inoculation (P<0.05). Howe ver, by day 12 post-inoculation, contractions to sarafotoxin S6c were not significantly different between control and virus-infected mice. I n parainfluenza-1-infected rats, there were small but significant redu ctions in the sensitivity to carbachol, endothelin-l and sarafotoxin S 6c whilst the maximal responses to the highest concentrations of these agonists were not significantly altered by virus infection (n=8). 5 B Q-123 (3 mu M) had no significant effect on cumulative concentration-e ffect curves to endothelin-l in tracheal preparations from control mic e (n=4) or parainfluenza-1-infected rats (n=8). In contrast, in tissue s taken from virus-infected mice at day 4 post-inoculation, BQ-123 cau sed a marked 9.6 fold rightward shift in the concentration-effect curv e to endothelin-l (n=4). 6 In summary, we have demonstrated that parai nfluenza-l infection in mice transiently reduced the density of trache al airway smooth muscle ET(B) receptors and this was reflected in redu ced responsiveness to the ET(B) receptor-selective agonist sarafotoxin S6c. In contrast, whilst parainfluenza-l infection in rats was associ ated with the pathological features and bronchial hyperresponsiveness common to respiratory tract viral infection, there was no selective do wn-regulation of ET(B) receptor expression or functional activity. The reasons for these species differences are not clear, but may relate t o differences in the airway inflammatory response to parainfluenza-l v irus.