Epithelial modulation of airway smooth muscle response to endothelin-1.
We investigated the role of epithelial modulation of contraction caused by endothelin-1 in airway smooth muscle in guinea pigs in situ. Airway responses were assessed isometrically as tracheal force and simultaneously as change in lung resistance. Intravenous administration of 10(-8) mol/kg endothelin-1 caused a biphasic response in tracheal active tension: initial relaxation (-0.82 +/- 0.22 g/cm after 30 s, p less than 0.05 versus baseline) followed by contraction (1.65 +/- 0.28 g/cm after 7 min, p less than 0.05 versus baseline). Endothelin-1 also elicited immediate bronchoconstriction; lung resistance increased from 0.148 +/- 0.030 to 0.992 +/- 0.274 cm H2O/L/s (p less than 0.005) after 10(-8) mol/kg endothelin-1 given intravenously. Active tension elicited by 10(-8) mol/kg endothelin-1 after removal of the epithelium from the tracheal segment (0.59 +/- 0.16 g/cm) was less than in segments with an intact epithelium (1.65 +/- 0.28 g/cm, p less than 0.01). Both tracheal contraction and bronchoconstriction were attenuated by pretreatment with indomethacin orally, BW 755C intravenously, or substitution of endothelin-C-terminal hexapeptide for endothelin-1. However, the initial tracheal relaxation response was similar after each intervention. These data suggest actions of endothelin-1 that have not been demonstrated previously: (1) endothelin-1 elicits a biphasic response in tracheal smooth muscle (an initial relaxation response elicited by the carboxy-terminal residues and a later contractile response that requires synthesis of a cyclooxygenase mediator) and (2) epithelium adjacent to the airway smooth muscle modulates contraction elicited by endothelin-1.
White
S R
SR
Section of Pulmonary and Critical Care Medicine, University of Chicago, Illinois.
Hathaway
D P
DP
Umans
J G
JG
Tallet
J
J
Abrahams
C
C
Leff
A R
AR
D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects*; D016232:Endothelins / Q000494:pharmacology / Q000502:physiology*; D004848:Epithelium / Q000502:physiology; D006168:Guinea Pigs; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D014132:Trachea / Q000187:drug effects* / Q000502:physiology
D016232:Endothelins; D007213:Indomethacin