Characterization of the endothelin receptor subtype mediating epithelium-derived relaxant nitric oxide release from guinea-pig trachea.
1. The endothelin (ET) receptor subtype that mediates niric oxide (NO)-dependent airway relaxation in tracheal tube preparations precontracted with carbachol and pretreated with indomethacin was investigated. The release of NO induced by ET from guinea-pig trachea using a recently developed porphyrinic microsensor was also measured. 2. ET-1 (1 pM-100 nM) contracted tracheal tube preparations pretreated with the NO-synthase inhibitor, L-NMMA, and relaxed, in an epithelium-dependent manner, preparations pretreated with the inactive enantiomer D-NMMA. The effect of L-NMMA was reversed by L-Arg, but not by D-Arg. 3. The selective ET(B) receptor agonists, IRL 1620 or sarafotoxin S6c, both (1 pM-100 nM) contracted tracheal tube preparations in a similar manner either after treatment with D-NMMA or with L-NMMA. In the presence of the ET(A) receptor antagonist, FR139317 (10 microM), ET-1 administration resulted in a contraction that was similar after either L-NMMA or D-NMMA. In the presence of the ET(B) receptor antagonist, BQ788 (1 microM), ET-1 relaxed and contracted tracheas pretreated with D-NMMA and L-NMMA, respectively. 4. Exposure of tracheal segments to ET-1 (1-1000 nM) caused a concentration-dependent increase in NO release that was reduced by L-NMMA. IRL1620 (1 microM) did not cause any significant NO release. FR139317 (10 microM), but not, BQ788 (1 microM), inhibited the NO release induced by ET-1. 5. These results demonstrate that in the isolated guinea-pig trachea activation of ET(B) receptors results in a contractile response, whereas activation of ET(A) receptors cause both a contraction, and an epithelium-dependent relaxation that is mediated by NO release.
Emanueli
C
C
Department of Experimental and Clinical Medicine, University of Ferrara, Italy.
Ricciardolo
F
F
Vergnani
L
L
Bertrand
C
C
Ricci
F
F
Manzoli
N
N
Folkerts
G
G
Nijkamp
F P
FP
Geppetti
P
P
D000818:Animals; D019332:Endothelin-1 / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism*; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000819:agonists / Q000145:classification / Q000378:metabolism*; D014132:Trachea / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D019323:omega-N-Methylarginine / Q000494:pharmacology
D019332:Endothelin-1; D004791:Enzyme Inhibitors; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D019323:omega-N-Methylarginine; D009569:Nitric Oxide