Effect of phospholipase C inhibitor U-73122 on antigen-induced airway smooth muscle contraction in guinea pigs.
The importance of phospholipase C (PLC) in airway smooth muscle contraction was studied, using an inhibitor of PLC, 1-[6-[[17 beta-3-methoxyestra-1,3,5(10)-trien-17-yl] amino]hexyl]-1H-pyrrole-2,5-dione (U-73122). Tracheas from ovalbumin (OA)-sensitized guinea pigs contracted rapidly after exposure to low concentrations of antigen (OA). However, tracheas treated with U-73122 for 10 min prior to the addition of antigen, demonstrated a 3 log rightward shift in the OA dose-response curve with an IC50 of 7 microM. The analogue of U-73122, 1-[6[[17 beta-3-methoxyestra-1,3,5 trien-17-yl]amino]hexyl]-2,5-pyrrolidine-dione (U-73433), was approximately 5-fold less active in inhibiting smooth muscle contraction. In addition to the inhibition of antigen-induced smooth muscle contraction, U-73122 inhibited carbachol- and leukotriene D4-induced smooth muscle contraction. Furthermore, U-73122 inhibited in a dose-dependent manner antigen-induced histamine release from guinea pig tracheal tissue. The inhibition of smooth muscle contraction by U-73122 correlated well with the inhibition of polyphosphoinositide mediates smooth muscle contractile responses to muscarinic agonists and leukotrienes as well as antigenic-induced contraction.
Department of Medicine, University of British Columbia, Vancouver, Canada.
H
H
Salari
A
A
Bramley
J
J
Langlands
S
S
Howard
M
M
Chan-Yeung
H
H
Chan
R
R
Schellenberg
D000818:Animals; D000941:Antigens / Q000276:immunology; D002217:Carbachol / Q000494:pharmacology; D002463:Cell Membrane Permeability; D004305:Dose-Response Relationship, Drug; D004963:Estrenes / Q000494:pharmacology*; D006168:Guinea Pigs; D006868:Hydrolysis; D066298:In Vitro Techniques; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000201:enzymology / Q000276:immunology / Q000502:physiology*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D011760:Pyrrolidinones / Q000494:pharmacology*; D014132:Trachea / Q000276:immunology / Q000502:physiology*; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000502:physiology*
D000941:Antigens; D004963:Estrenes; D018129:Phosphatidylinositol Phosphates; D011760:Pyrrolidinones; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D002217:Carbachol; D010738:Type C Phospholipases