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)
Center for Experimental Therapeutics, Baylor College of Medicine, Houston, Texas.
K J
KJ
Morrison
P M
PM
Vanhoutte
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