Mast cell tryptase causes airway smooth muscle hyperresponsiveness in dogs.
Supernatants obtained by degranulation of dog mastocytoma cells greatly increased the sensitivity and the magnitude of the contractile response of isolated dog bronchial smooth muscle to histamine. The enhanced contractile response was reversed completely by H1-receptor antagonists and was prevented by an inhibitor of tryptase (a major protease released with histamine from secretory granules of mast cells). The potentiation of histamine-induced contractions was reproduced by active tryptase in pure form. The contractions due to the combination of histamine and purified tryptase were abolished by the Ca2+ channel blockers nifedipine and verapamil. The bronchoconstricting effects of KCl and serotonin, which, like histamine, contract airway smooth muscle by a mechanism predominantly involving membrane potential-dependent Ca2+ transport, were also potentiated by tryptase. However, the contractile effects of acetylcholine, which contracts dog airway smooth muscle by a mechanism independent of Ca2+ channels, were unaffected by tryptase. These findings show a striking promotion of agonist-induced bronchial smooth muscle contraction by mast cell tryptase, via direct or indirect effects on Ca2+ channels, and the findings therefore suggest a novel potential mechanism of hyperresponsiveness in dog bronchi.
Sekizawa
K
K
Department of Medicine, University of California, San Francisco 94143.
Caughey
G H
GH
Lazarus
S C
SC
Gold
W M
WM
Nadel
J A
JA
D000403:Airway Resistance / Q000187:drug effects*; D000818:Animals; D004285:Dogs; D004357:Drug Synergism; D006632:Histamine / Q000494:pharmacology; D008407:Mast Cells / Q000201:enzymology*; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D009543:Nifedipine / Q000494:pharmacology; D010447:Peptide Hydrolases / Q000378:metabolism*; D011189:Potassium Chloride / Q000494:pharmacology; D012701:Serotonin / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
D012701:Serotonin; D011189:Potassium Chloride; D006632:Histamine; D014700:Verapamil; D010447:Peptide Hydrolases; C023073:tosylarginine methyl ester hydrolase; D009543:Nifedipine