The role of endothelin in mediating virus-induced changes in endothelinB 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 associated with increased levels of ET and altered ET receptor density and function in murine airways. To determine whether these virus-induced effects are causally linked, perhaps involving ET-1-induced ET(B) receptor downregulation, the current study investigated the influence of in vivo administration of CGS 26303, an ET-converting enzyme inhibitor, on virus-induced changes in ET-content and ET(B) receptor density. CGS 26303 (5 mg x kg(-1) x day(-1)) or placebo was administered to mice via osmotic minipumps implanted subcutaneously. Two days after implantation, mice were inoculated with influenza A/PR-8/34 virus or sham-infected, and all measurements were performed on tissue obtained on the fourth day post-inoculation. Viral infection was associated with elevated levels of immunoreactive ET and decreased densities of ET(B) receptors in murine airways. Both of these effects were attenuated in virus-infected mice that had received CGS 26303. Virus-induced increases in wet lung weight were also inhibited by CGS 26303. Importantly, administration of CGS 26303 had no effect on the titres of infectious 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 immunoreactive endothelin content and endothelinB receptor density. These findings are consistent with the postulate that the elevated epithelial expression of endothelin-1 during respiratory tract viral infection is a contributing factor in the downregulation of endothelinB receptors in airway smooth muscle. Whether inhibitors of endothelin synthesis attenuate virus-induced exacerbations of asthma or airways hyperresponsiveness remains to be established.
Henry
P J
PJ
Dept of Pharmacology, University of Western Australia, Nedlands, Australia.
Carr
M J
MJ
Goldie
R G
RG
Jeng
A Y
AY
D000818:Animals; D001345:Autoradiography; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D019332:Endothelin-1 / Q000502:physiology*; D009980:Influenza A virus / Q000187:drug effects / Q000302:isolation & purification / Q000472:pathogenicity*; D008168:Lung / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D009130:Muscle, Smooth / Q000378:metabolism / Q000473:pathology / Q000821:virology; D015260:Neprilysin / Q000037:antagonists & inhibitors; D009929:Organ Size; D063065:Organophosphonates / Q000493:pharmacokinetics; D009976:Orthomyxoviridae Infections / Q000188:drug therapy / Q000378:metabolism* / Q000821:virology; D011480:Protease Inhibitors / Q000493:pharmacokinetics; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000187:drug effects / Q000378:metabolism*; D013777:Tetrazoles / Q000493:pharmacokinetics; D014132:Trachea / Q000378:metabolism* / Q000473:pathology / Q000821:virology
D019332:Endothelin-1; D063065:Organophosphonates; D011480:Protease Inhibitors; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D013777:Tetrazoles; C089987:CGS 26303; D015260:Neprilysin