Direct effects and augmentation of airway smooth muscle contraction caused by phospholipase A2.
We examined the effect of phospholipase A2 (PLA2; Naja naja) on isometric tracheal smooth muscle force generation in guinea pig trachealis in situ. Direct application of PLA2 to the surface of the trachea caused dose-related contraction of tracheal smooth muscle. In seven guinea pigs, a dose/density of 100 micrograms/cm2 PLA2 caused active tension (AT) that began immediately and was maximum (1.32 +/- 0.13 g/cm) at 5 min (p less than 0.01 versus baseline tension). PLA2 also augmented the contractile response to intravenously administered acetylcholine (ACh); AT caused by 3 x 10(-7) mol/kg ACh was 0.98 +/- 0.13 g/cm after PLA2 versus 0.64 +/- 0.09 g/cm in control animals (p = 0.003). PLA2 inactivated with bromophenacyl bromide (BPB) prior to topical application neither caused contraction (-0.18 +/- 0.18 g/cm AT, p = NS versus baseline tension) nor altered muscarinic responsiveness to 3 x 10(-7) mol/kg ACh. Contraction caused by 100 micrograms/cm2 PLA2 was greater after epithelium removal (2.73 +/- 0.40 g/cm AT versus 1.32 +/- 0.13 g/cm AT in epithelium-intact animals, p less than 0.005). However, epithelium removal (confirmed histologically) attenuated completely augmentation of muscarinic contraction caused by PLA2. Augmentation of muscarinic contraction also was blocked with 15 mg/kg 3-amino-1-(3-trifluoromethylphenyl)-2-pyrazoline hydrochloride (BW 755c), an inhibitor of eicosanoid synthesis, administered intravenously 30 min prior to topical application of 100 micrograms/cm2 PLA2. In contrast, contraction of tracheal smooth muscle caused by PLA2 was not affected significantly by blockade of eicosanoid synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)
Strek
M E
ME
Department of Medicine, University of Chicago, Illinois 60637.
Garland
A
A
Abrahams
C
C
Leff
A R
AR
White
S R
SR
D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine / Q000494:pharmacology; D000098:Acetophenones / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D015777:Eicosanoids / Q000378:metabolism; D006168:Guinea Pigs; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D054467:Phospholipases A2; D011976:Receptors, Muscarinic / Q000502:physiology; D014132:Trachea / Q000187:drug effects / Q000502:physiology
D000098:Acetophenones; D015777:Eicosanoids; D011976:Receptors, Muscarinic; D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D010741:Phospholipases A; D054467:Phospholipases A2; D000109:Acetylcholine; C006821:4-bromophenacyl bromide