Tachykinin antagonist FK224 inhibits neurokinin A-, substance P- 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 studied the effects of tachykinin antagonist FK224 on bronchial smooth muscle contraction induced by SP, NKA and capsaicin in an organ bath. FK224 (10(-6) M and 10(-5) M, respectively) significantly inhibited NKA-induced contraction and 10(-5) M FK224 shifted the dose-response curve to more than one log unit higher concentration. Because SP- and capsaicin-induced contractions were small, we pretreated the tissues with the neutral endopeptidase inhibitor phosphoramidon (10(-5) M), which inhibits degradation of exogenous tachykinins in order to potentiate the contractions. FK224 (10(-5) M) significantly inhibited SP-induced contraction and it shifted the dose-response curves to about one log unit higher concentration. FK224 (10(-5) M) also significantly inhibited capsaicin-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 D4-induced contraction. These results suggest that FK224 is a tachykinin receptor antagonist in the human bronchial smooth muscle, and that capsaicin-induced contraction is due to endogenously released tachykinin-like substances in the human bronchus.
Honda
I
I
First Department of Internal Medicine, Kumamoto University School of Medicine, Japan.
Kohrogi
H
H
Yamaguchi
T
T
Hamamoto
J
J
Hirata
N
N
Iwagoe
H
H
Fujii
K
K
Goto
E
E
Ando
M
M
D000109:Acetylcholine / Q000494:pharmacology; D000328:Adult; D000368:Aged; D001980:Bronchi / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D002211:Capsaicin / Q000494:pharmacology*; D006020:Glycopeptides / Q000494:pharmacology; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D017998:Leukotriene D4 / Q000494:pharmacology; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D015288:Neurokinin A / Q000378:metabolism / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology; D018039:Receptors, Tachykinin / Q000037:antagonists & inhibitors*; D013373:Substance P / Q000378:metabolism / Q000494:pharmacology; D015320:Tachykinins / Q000378:metabolism / Q000494:pharmacology*
D006020:Glycopeptides; D010456:Peptides, Cyclic; D011480:Protease Inhibitors; D018039:Receptors, Tachykinin; D015320:Tachykinins; C075570:FK 224; D013373:Substance P; D017998:Leukotriene D4; D006632:Histamine; D015288:Neurokinin A; D000109:Acetylcholine; D002211:Capsaicin; C008890:phosphoramidon