Inhibition of airway smooth muscle tone by a phorbol ester in the guinea pig trachea: role of epithelium and receptor reserve of the contractile agent.
Bronchial hyperresponsiveness in patients with asthma may be associated with a damaged or dysfunctional epithelium. Also, changes in the activities of protein kinase C have been implicated in the pathogenesis of asthma. This study examined the role of protein kinase C in the modulation of airway smooth muscle tone and the influence of the epithelium on this function. Phorbol-12,13-diacetate (PDA) (10(-8) to 10(-5) M) induced concentration-dependent and epithelium-independent relaxations of guinea pig tracheal rings. PDA (10(-8) to 10(-5) M) induced significantly greater relaxations of tracheal rings contracted with 5-hydroxytryptamine (10(-5) M) than in tissues contracted to an equivalent degree with acetylcholine (10(-6) M). In experiments using phenoxybenzamine (10(-7) M and 10(-5) M), the dissociation constant (KA) for acetylcholine was significantly greater than that for 5-hydroxytryptamine. The fraction of active receptors (q) calculated for acetylcholine was significantly smaller than that calculated for an equieffective concentration of 5-hydroxytryptamine. Relaxations to PDA in tissues contracted with acetylcholine (2 x 10(-6) M) or 5-hydroxytryptamine (10(-5) M) were significantly augmented by phenoxybenzamine (10(-5) M and 10(-7) M, respectively). PDA did not affect contractions to acetylcholine (10(-8) to 10(-3) M) in the presence of epithelium but caused a significant right-ward displacement of the acetylcholine concentration-contraction curve in the absence of epithelium. The concentration-contraction curves for 5-hydroxytryptamine (10(-8) to 10(-5) M) were significantly displaced to the right by PDA in the presence or absence of epithelium. This effect was greater in the absence of epithelium.(ABSTRACT TRUNCATED AT 250 WORDS)
Morrison
K J
KJ
Center for Experimental Therapeutics, Baylor College of Medicine, Houston, Texas.
Vanhoutte
P M
PM
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D004347:Drug Interactions; D004848:Epithelium / Q000502:physiology; D006168:Guinea Pigs; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000201:enzymology; D009569:Nitric Oxide / Q000502:physiology*; D010208:Papaverine / Q000494:pharmacology; D010703:Phorbol Esters / Q000494:pharmacology*; D011493:Protein Kinase C / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects / Q000201:enzymology
D010703:Phorbol Esters; D009569:Nitric Oxide; D012701:Serotonin; D010208:Papaverine; D011493:Protein Kinase C; D000109:Acetylcholine