Direct effects on airway smooth muscle contractile response caused by endothelin-1 in guinea pig trachealis.
Endothelin-1 (ET-1), a peptide derived from vascular endothelial cells, causes tracheal smooth muscle (TSM) relaxation followed by sustained contraction when administered intravenously in guinea pigs by a mechanism that depends upon an intact airway epithelium. To elucidate the potential role of the epithelium in modulating the response to ET-1 and the potential effects of local release of ET-1, we studied the effects of topical application of ET-1 to a segment of TSM in situ. An epithelium smooth muscle preparation that does not disrupt normal anatomic relationships was used; smooth muscle contraction was measured isometrically in vivo. Application of 10(-10) mol/cm2 ET-1 to the epithelial surface in six animals caused 2.27 +/- 0.45 g/cm active tension (AT) of the TSM segment after 30 min (p less than 0.05 versus baseline); an initial relaxation response was not observed. Endothelin-1 was dose-dependent and was 1,000 times more potent than acetylcholine in causing AT in TSM. Pretreatment with ET-1 did not alter the subsequent response to acetylcholine. Contraction elicited by topical application of ET-1 persisted greater than 3 h. In five animals in which the epithelium was removed, 10(-10) mol/cm2 ET-1 caused 4.45 +/- 0.92 g/cm AT after 30 min (p less than 0.05 versus intact epithelium). These data suggest that topical application of ET-1 elicits responses that are different from those elicited in the same preparation after intravenously administered ET-1: (1) TSM contraction that is not preceded by a transient relaxation phase, and (2) contraction that is not reduced after removal of the epithelium.
White
S R
SR
Department of Medicine, University of Chicago, Illinois 60637.
Hathaway
D P
DP
Umans
J G
JG
Leff
A R
AR
D000109:Acetylcholine / Q000494:pharmacology; D000287:Administration, Topical; D000818:Animals; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000008:administration & dosage / Q000494:pharmacology*; D006168:Guinea Pigs; 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; D000109:Acetylcholine