Role of thromboxane receptor activation in the bronchospastic response to endothelin.
The selective TxA2/PGH2 (TP) receptor antagonist, SQ 30,741, was used to test the hypothesis that TP-receptor activation contributes to the reactivity of airways and isolated trachea to endothelin-1 (ET-1). Dose-dependent contractions of guinea pig tracheal strips to ET-1 in vitro were unaffected by either SQ 30,741 (1 microM) or indomethacin (2.8 microM). In contrast, maximal bronchospastic responses (increases in airways resistance and decreases in dynamic lung compliance) of anesthetized guinea pigs to ET-1 (0.5 and 1.5 nmole/kg i.v.) in vivo were blocked greater than 90% by SQ 30,741 (1 mg/kg i.v.). Concurrent increases in arterial blood pressure and decreases in leukocyte counts induced by ET-1 were unaffected by SQ 30,741. In rats, ET-1 (1.5 nmole/kg i.v.) did not affect lung mechanics, but did cause biphasic blood pressure and leukopenia responses which were unaltered by SQ 30,741. These data demonstrate that there is considerable species variability in the bronchospastic response to ET-1, and that in guinea pigs, this response is caused predominantly by the activation of TP-receptors.
Schumacher
W A
WA
Department of Pharmacology, Squibb Institute for Medical Research, Princeton, NJ 08543-4000.
Steinbacher
T E
TE
Allen
G T
GT
Ogletree
M L
ML
D000818:Animals; D001986:Bronchial Spasm / Q000139:chemically induced* / Q000378:metabolism; D016232:Endothelins; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011982:Receptors, Prostaglandin / Q000187:drug effects*; D017482:Receptors, Thromboxane; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013931:Thromboxanes; D014132:Trachea / Q000187:drug effects
D016232:Endothelins; D010455:Peptides; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D013931:Thromboxanes; C054215:SQ 30741; D013928:Thromboxane A2