EVIDENCE FOR FUNCTIONAL TACHYKININ NK1 RECEPTORS ON HUMAN ISOLATED SMALL BRONCHI

On human small isolated bronchi (diameter <1 mm), but not on larger br onchi (diameter 3-5 mm), substance P (SP) and specific tachykinin SP-p referring neurokinin (NK1) receptor agonists {[beta Ala(4),Sar(9),Met( O-2)(11)]SP-(4-11), [Sar(9),Met(O-2)(11)]SP, [Arg(6),Sar(9),Met(O-2)(1 1)] P-(6-11), and septide; 10(-10) to 10(-6) M} produced a concentrati on-dependent contraction that occurred at low concentrations (pot valu es of 7.79-8.33) and was characterized by a low intrinsic activity [ma ximal effect (E(max)) of 38-45% of E(max) induced by 3 mill acetylchol ine, in a noncumulative manner]. Comparison of cumulative and noncumul ative concentration-response curves to SP and NK1 receptor agonists su ggest rapid receptor desensitization. The SP (10(-8) M)-induced contra ction was inhibited by tachykinin NK1 receptor antagonists (rank order of potency: SR-140333 > CP-96,345 > RP-67580) but not by the tachykin in NK2 receptor antagonist SR-48968. Indomethacin (10(-6) M) abolished the SP-induced contraction. Our results suggest that tachykinin NK1 r eceptors are present on human small bronchi and that their stimulation induces a prostanoid-dependent contraction. The small isolated bronch us is an interesting model of human tissue to test NK1 receptor antago nists.