The role of endothelin in mediating virus-induced changes in endothelin(B)receptor density in mouse airways

Emerging evidence supports a mediator role for endothelin (ET)-1 in airway diseases including asthma. Respiratory tract viral infections, are associat ed with increased levels of ET and altered ET receptor density and function in murine airways. To determine whether these virus-induced effects are ca usally linked, perhaps involving ET-1-induced ETB receptor downregulation, the current study investigated the influence of in vivo administration of C GS 26303, an ET-converting enzyme inhibitor, on virus-induced changes in ET -content and ETB receptor density. CGS 26303 (5 mg.kg(-1)day(-1)) or placebo was administered to mice via osmo tic minipumps implanted subcutaneously. Two days after implantation, mice w ere inoculated with influenza A/PR-8/34 virus or sham-infected, and all mea surements were performed on tissue obtained on the fourth day post-inoculat ion. Viral infection was associated with elevated levels of immunoreactive ET an d decreased densities of ETB receptors in murine airways. Both of these eff ects were attenuated in virus-infected mice that had received CGS 26303. Vi rus-induced increases in wet lung weight were also inhibited by CGS 26303. Importantly, administration of CGS 26303 had no effect on the titres of inf ectious virus in the lungs and similarly, viral infection had no effect on the plasma levels of free CGS 26303. In summary, CGS 26303 inhibited the virus-induced changes in both immunorea ctive endothelin content and endothelin(B) receptor density. These findings are consistent,vith the postulate that the elevated epithelial expression of endothelin-1 during respiratory tract viral infection is a contributing factor in the downregulation of endothelin(B) receptors in airway smooth mu scle. Whether inhibitors of endothelin synthesis attenuate virus-induced ex acerbations of asthma or airways hyperresponsiveness remains to be establis hed.