The effect of chronic hypoxia on endothelin receptor subtype-mediated responses in rat isolated airways.
Contractile responses to endothelin-1 (ET-1) were investigated in isolated trachea from rats previously exposed to chronic hypoxia (10% O(2)) or room air for 14 days. Concentration-response curves were constructed to ET-1 (10(-11)-3x10(-7)m ) in the presence and absence of the ET(A)receptor antagonist FR 139317 (10(-8), 10(-7)and 10(-6)m ), the ET(B)receptor antagonist BQ 788 (10(-6)and 3x10(-6)m ), the non-selective ET receptor antagonist SB 209670 (10(-7)and 10(-6)m ) and a combination of FR 139317 (10(-6)m ) and BQ 788 (10(-6)m ). Concentration-response curves were also conducted to the ET(B)receptor agonist sarafotoxin S6c (10(-11)-3x10(-7)m ). In addition, responses to ET-1 (10(-11)-3x10(-7)m ) were examined in the presence and absence of the nitric oxide synthase inhibitor, L-NAME. In control rat trachea, both FR 139317 and BQ 788 failed to inhibit ET-1-induced contractions and, indeed, FR 139317 (10(-8)m ) and BQ 788 actually potentiated responses. In trachea from chronic hypoxic rats, FR 139317 did not alter ET-1 responses whereas BQ 788 again potentiated ET-1-induced contractions. The non-selective ET receptor antagonist SB 209670 attenuated ET-1-evoked contractions in trachea from control and chronically hypoxic rats. A combination of FR 139317 (10(-6)m ) and BQ 788 (10(-6)m ) also attenuated ET-1 responses in control rat trachea, but not trachea from chronically hypoxic rats. In trachea from both control and chronically hypoxic rats, L-NAME significantly potentiated responses to ET-1. To investigate ET receptor-mediated relaxation, tissues were preconstricted with methacholine and concentration-response curves were conducted to ET-1 (10(-13)-10(-8)m ) in the presence and absence of BQ 788 (10(-6)m ) and to the ET(B)receptor agonist sarafotoxin S6c (10(-13)-10(-8)m ). In trachea from control and chronic hypoxic rats, ET-1 and sarafotoxin S6c evoked only very small, non-reproducible relaxatory responses.
Division of Neuroscience and Biomedical Systems, Institute of Biomedical and Life Sciences, Glasgow, G12 8QQ, UK.
R A
RA
Clayton
J E
JE
Nally
M R
MR
MacLean
N C
NC
Thomson
J C
JC
McGrath
D000818:Animals; D001249:Asthma / Q000503:physiopathology*; D016084:Bronchoconstriction / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000494:pharmacology*; D000860:Hypoxia / Q000503:physiopathology*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017466:Receptors, Endothelin / Q000502:physiology*; D014132:Trachea / Q000502:physiology*
D019332:Endothelin-1; D017466:Receptors, Endothelin; D019331:NG-Nitroarginine Methyl Ester