Neurokinin A-induced contraction of guinea-pig isolated trachea: potentiation by hepoxilins.
1. Hepoxilin A3 (8R and 8S isomers) (HxA3), hepoxilin A3-C (8R and 8S isomers) (HxA3-C) and trioxilin A3 (8S isomer) (TrXA3, the stable derivative of HxA3) were tested for their effects on helicoidal strips of guinea-pig isolated tracheae. 2. None of the compounds (10(-9)-10(-6) M) tested had a direct effect on resting tension of trachea. 3. HxA3 (8S) and HxA3-C (8R) (10(-8) M) produced a significant leftward shift of the log concentration-response curves to neurokinin A (NKA) (EC50 (nM), control = 29.0 +/- 2.8, HxA3 (8S) = 21.7 +/- 3.7, HxA3-C (8R) = 13.8 +/- 3.8, n = 6 for each). Also the maximal response to NKA was significantly increased when the tissues were exposed to these hepoxilins (% of the maximal response to NKA, control = 100, HxA3 (8S) = 114.5 +/- 5.3, HxA3-C (8R) = 139.0 +/- 6.2, n = 6 for each). The threshold concentrations for both hepoxilins was 10(-8) M and their effects were dose-related. 4. Stereochemical specificity was observed. The 8S-isomer of HxA3 was active in potentiating the NKA-induced contraction of the trachea while the 8R isomer was inactive. In contrast, the 8R isomer of HxA3-C was active while the 8S isomer was inactive. The trihydroxy metabolite of the active isomer of HxA3 (8S), i.e. TrXA3 (8S) (10(-6) M), was inactive in potentiating the NKA-induced contraction of the trachea. 5. It is concluded that hepoxilins sensitize the guinea-pig isolated trachea to the potent bronchoconstrictor, NKA.
Laneuville
O
O
Research Institute, Hospital for Sick Children, Toronto, Canada.
Couture
R
R
Pace-Asciak
C R
CR
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects; D004357:Drug Synergism; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D015288:Neurokinin A / Q000494:pharmacology*; D013237:Stereoisomerism; D014132:Trachea / Q000187:drug effects
C038243:8-hydroxy-11,12-epoxyeicosa-5,9,14-trienoic acid; D015288:Neurokinin A; D015126:8,11,14-Eicosatrienoic Acid