Endothelin-1 induced bronchial hyperresponsiveness in the rabbit: an ET(A) receptor-mediated phenomenon.
Endothelin-1 (ET-1) is a potent and efficacious spasmogen of airway smooth muscle. Recent observations suggest that an increased intrapulmonary production of ET-1 may occur in asthma. Our previous study showed that endothelin-1 induced bronchial hyperresponsiveness to inhaled histamine in the rabbit. The aim of this study was to investigate whether the ET(A) and ET(B) receptors mediate the bronchial hyperresponsiveness induced by endothelin-1 in the rabbit. Our data showed that bronchial hyperresponsiveness induced by ET-1 was significantly inhibited (P<0.01) by the ET(A) receptor-selective antagonist, FR 139317 (from 2.5 to 10 mg kg(-1)). Moreover, bosentan (from 2.5 mg kg(-1) to 10 mg kg(-1)), an ET(A)/ET(B) receptor antagonist, also inhibited the bronchial hyperresponsiveness achieved 24 h following endothelin-1 challenge (P<0.01), but with no difference from FR 139317. The ET(B) receptor agonist, sarafotoxin S6c (from 25 microg to 2.5 mg kg(-1)) did not modify airway responsiveness to inhaled histamine in the rabbit. These results indicate that bronchial hyperresponsiveness induced by ET-1 may be mediated by ET(A) receptor activation.
D'Agostino
B
B
Institute of Pharmacology and Toxicology, Faculty of Medicine and Surgery, 2nd University of Naples, Italy. brdagost@unina.it
Gallelli
L
L
Falciani
M
M
Di Pierro
P
P
Rossi
F
F
Filippelli
A
A
Rossi
F
F
D000280:Administration, Inhalation; D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage; D001381:Azepines / Q000008:administration & dosage; D000077300:Bosentan; D001980:Bronchi / Q000187:drug effects* / Q000378:metabolism*; D016084:Bronchoconstriction / Q000187:drug effects / Q000502:physiology; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000008:administration & dosage* / Q000378:metabolism*; D005260:Female; D006632:Histamine; D007211:Indoles / Q000008:administration & dosage; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism*; D011817:Rabbits; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000819:agonists / Q000378:metabolism*; D012130:Respiratory Hypersensitivity / Q000139:chemically induced / Q000175:diagnosis / Q000503:physiopathology*; D013449:Sulfonamides / Q000008:administration & dosage; D014662:Vasoconstrictor Agents / Q000008:administration & dosage; D014757:Viper Venoms / Q000008:administration & dosage
D000959:Antihypertensive Agents; D001381:Azepines; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D007211:Indoles; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D013449:Sulfonamides; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; C079574:FR 139317; D006632:Histamine; D000077300:Bosentan