Inhibition of neutral endopeptidase potentiates compound 48/80-induced constriction of guinea-pig tracheal smooth muscle.
Our previous studies have shown that the inhibition of neutral endopeptidase, an enzyme which degrades tachykinins, increases anaphylactic construction of guinea-pig tracheal smooth muscle. To investigate this observation further, we examined the effects of phosphoramidon, an inhibitor of a neutral endopeptidase, on constriction induced by the non-immunological mast cell degranulator-compound 48/80. Phosphoramidon produced significant leftward shift of the compound 48/80 concentration-response curve with corresponding decrease in the EC50 value from 51 (28-80) micrograms/ml to 42 (20-72) micrograms/ml. When added during the compound 48/80-induced constriction, phosphoramidon significantly increased the magnitude of this constriction by 69.7% after 30 min, and 78.9% after 45 min. Phosphoramidon was ineffective in tracheal rings from tachykinin-depleted guinea pigs. The incubation of tracheal rings with H1-histamine receptor antagonist (diphenhydramine HCl, 10 microM) and leukotriene receptor antagonist (ICI 198.615, 5 microM) significantly diminished the contractile response to compound 48/80 and prevented a phosphoramidon-dependent increase of this constriction. These results suggest that compound 48/80 induces the release of tachykinins by the stimulatory activity of histamine and leukotrienes. Anaphylactic release of tachykinins would therefore not depend directly on the antigen-antibody reaction.
Tudoric
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Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, USA.
Coon
R L
RL
Bosnjak
Z J
ZJ
D000707:Anaphylaxis / Q000378:metabolism; D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D005260:Female; D006020:Glycopeptides / Q000494:pharmacology; D006168:Guinea Pigs; D006636:Histamine Release / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology*; D015320:Tachykinins / Q000494:pharmacology; D013997:Time Factors; D014132:Trachea / Q000187:drug effects*; D003189:p-Methoxy-N-methylphenethylamine / Q000494:pharmacology*
D006020:Glycopeptides; D011480:Protease Inhibitors; D015320:Tachykinins; D003189:p-Methoxy-N-methylphenethylamine; D015260:Neprilysin; D002211:Capsaicin; C008890:phosphoramidon