TACHYKININ ANTAGONIST FK224 INHIBITS NEUROKININ-A-INDUCED, SUBSTANCE-P-INDUCED AND CAPSAICIN-INDUCED HUMAN BRONCHIAL CONTRACTION

To determine the roles of endogenously released tachykinins (substance P [SP] and neurokinin A [NKA]) in the human bronchial tissues, we stu died the effects of tachykinin antagonist FK224 on bronchial smooth mu scle contraction induced by SP, NKA and capsaicin in an organ bath. FK 224 (10(-6) M and 10(-5) M, respectivly) significantly inhibited NKA-i nduced contraction and 10(-5) M FK224 shifted the dose-response curve to more than one log unit higher concentration. Because SP- and capsai cin-induced contractions were small, we pretreated the tissues with th e neutral endopeptidase inhibitor phosphoramidon (10(-5) M), which inh ibits degradation of exogenous tachykinins in order to potentiate the contractions. FK224 (10(-5) M) significantly inhibited SP-induced cont raction and it shifted the dose-response curves to about one log unit higher concentration. FK224 (10(-5) M) also significantly inhibited ca psaicin-induced contraction and it shifted the dose-response curves to more than one log unit higher concentration. In contrast, FK224 (10(- 5) M) did not affect on acetylcholine-, histamine-, and leukotriene D- 4-induced contraction. These results suggest that FK224 is a tachykini n receptor antagonist in the human bronchial smooth muscle, and that c apsaicin-induced contraction is due to endogenously released tachykini n-like substances in the human bronchus.