Evidence for functional tachykinin NK1 receptors on human isolated small bronchi.
On human small isolated bronchi (diameter < 1 mm), but not on larger bronchi (diameter 3-5 mm), substance P (SP) and specific tachykinin SP-preferring neurokinin (NK1) receptor agonists {[beta Ala4, Sar9, Met(O2)11]SP-(4-11), [Sar9, Met(O2)11]SP, [Arg6,Sar9,Met(O2)11]SP-(6-11), and septide; 10(-10) to 10(-6) M} produced a concentration-dependent contraction that occurred at low concentrations (pD2 values of 7.79-8.33) and was characterized by a low intrinsic activity [maximal effect (Emax) of 38-45% of Emax induced by 3 mM acetylcholine, in a noncumulative manner]. Comparison of cumulative and noncumulative concentration-response curves to SP and NK1 receptor agonists suggest rapid receptor desensitization. The SP (10(-8) M)-induced contraction was inhibited by tachykinin NK1 receptor antagonists (rank order of potency: SR-140333 > CP-96,345 > RP-67580) but not by the tachykinin NK2 receptor antagonist SR-48968. Indomethacin (10(-6) M) abolished the SP-induced contraction. Our results suggest that tachykinin NK1 receptors are present on human small bronchi and that their stimulation induces a prostanoid-dependent contraction. The small isolated bronchus is an interesting model of human tissue to test NK1 receptor antagonists.
Naline
E
E
Laboratoire de Pharmacologie, Faculté de Médecine Paris Ouest, France.
Molimard
M
M
Regoli
D
D
Emonds-Alt
X
X
Bellamy
J F
JF
Advenier
C
C
D001549:Benzamides / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008175:Lung Neoplasms / Q000473:pathology / Q000601:surgery; D008297:Male; D008875:Middle Aged; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000494:pharmacology; D011812:Quinuclidines / Q000494:pharmacology; D018040:Receptors, Neurokinin-1 / Q000378:metabolism / Q000502:physiology*; D013373:Substance P / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*
D001549:Benzamides; D001713:Biphenyl Compounds; D006727:Hormone Antagonists; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D011812:Quinuclidines; D018040:Receptors, Neurokinin-1; C085215:SR 140333; D013373:Substance P; C073839:SR 48968; C066892:CP 96345; D007213:Indomethacin