DIFFERENTIAL BLOCKADE BY TACHYKININ NK1 AND NK2 RECEPTOR ANTAGONISTS OF BRONCHOCONSTRICTION INDUCED BY DIRECT-ACTING AGONISTS AND THE INDIRECT-ACTING MIMETICS CAPSAICIN, SEROTONIN AND 2-METHYL-SEROTONIN IN THEANESTHETIZED GUINEA-PIG

This study has examined the abilities of (+/-)-CP96345 and (+/-)-SR489 68, nonpeptide antagonists selective for the tachykinin NK1 and NK2 re ceptors, respectively, to block bronchoconstriction caused by intraven ous administration of direct-acting receptor agonists and the indirect -acting mimetics capsaicin, serotonin and 2-methyl-serotonin in the an esthetized guinea pig. The NK1 antagonist (+/-)CP96345 was found to ca use, at a maximally tolerated dose of 9 mumol/kg, an approximate 10-fo ld rightward shift of the dose-response curves for selective NK1 agoni sts substance P (SP), [Sar9,Met(O2)11]SP and Ac-[Arg6,Sar9, Met(O2)11S P6-11 without altering responses to selective NK2 agonists neurokinin A (NKA), [Nle10]NKA4-10 or [beta-Ala8]NKA4-10. The NK2 antagonist (+/- )-SR48968 caused dose-dependent rightward shifts of the dose-response curves for the NK2 but not the NK1 agonists. Results using combination s of the receptor antagonists indicate that the NK2 agonists could cau se bronchoconstriction by acting on the NK1 receptors at large doses r elative to those used without antagonists. Of the agonists used here, [beta-Ala8]NKA4-10 appeared to be the most selective for the NK2 recep tors. When used alone, only (+/-)-SR48968 was found to block bronchoco nstriction caused by capsaicin, serotonin (after blockade of 5-HT2 rec eptors by LY53857) and 2-methyl-serotonin. When (+/-)-CP96345 was also given, larger additional blockade was seen with capsaicin than with s erotonin or 2-methylserotonin as mimetic substance. Atropine caused sm all and variable degrees of blockade of serotonin and 2-methyl-seroton in but not of capsaicin after combinations of the two antagonists. The results support an involvement of tachykinin NK1 and NK2 receptors in mediating bronchoconstriction in the guinea pig and indicate that dif ferent proportions of these receptors are involved in this action when different indirect-acting mimetics are administered.