PHARMACOLOGICAL EXAMINATION OF RECEPTORS MEDIATING CONTRACTILE RESPONSES TO TACHYKININS IN AIRWAYS ISOLATED FROM HUMAN, GUINEA-PIG AND HAMSTER

The abilities of agonists selective for neurokinin (NK)-l (Ac-[Arg6,Sa r9,Met(O2)11]-SP6-11,ASMSP), NK-2([beta-Ala8]-NKA4-10) and NK-3 ([ASp5 ,6,MePhe8]-SP5-11, senktide analog) receptors to contract human bronch us and guinea pig and hamster trachea were studied. The antagonism of these responses by selective antagonists was also examined. In the hum an bronchus and hamster trachea, [beta-Ala8]-NKA4-1 0 was the most pot ent agonist, whereas ASMSP and senktide analog failed to elicit contra ctions greater than 50% of the maximum response even at concentrations reaching 1 to 3 x 10(-4) M. By contrast, both ASMSP and [beta-Ala8]-N KA4-1 0 were potent contractile agonists in guinea pig trachea. In all tissues, the selective NK-1 receptor antagonist yphenyl)-methyl]-1-az abicyclo-[2.2.2]octan-3-amine (CP 96,345) was without effect on contra ctile responses to [beta-Ala8]-NKA4-1 0. Blockade by CP 96,345 of resp onses to ASMSP was, however, observed in the guinea pig trachea, but n ot in human bronchus or hamster trachea. Responses to ASMSP in human b ronchus and hamster trachea were inhibited by NK-2 antagonists whereas these compounds had little effect on responses to ASMSP in guinea pig trachea. In all tissue types, responses to senktide analog were inhib ited by NK-2 antagonists. The NK-2 selective antagonists Ac-Leu-Asp-Gl y-Trp-Phe-Gly-NH2 (R 396) H-Asp-Tyr-D-Trp-Val-D-Trp-D-Trp-Lys-NH2 (MEN 10,376) and (S)-N-methyl-N[4-(4-acetylamino-4-phenyl piperidino)-2-(3 ,4-dichlorophenyl)butyl] benzamide (SR 48,968) blocked responses to [b eta-Ala8]-NKA4-10 in human bronchus, guinea pig trachea and hamster tr achea. The rank order of potency in human bronchus was SR 48,968 > MEN 10,376 greater-than-or-equal-to R 396. A similar order was obtained i n the guinea pig trachea (SR 48,968 > MEN 10,376 > R 396), whereas in the hamster trachea, the rank order of potency was SR 48,968 > R 396 > MEN 10,376. These results suggest that tachykinin-induced contraction s of human bronchus and hamster trachea are mediated by only NK-2-type receptors, whereas contractions of the guinea pig trachea involve act ivation of both NK-1- and NK-2-type receptors. Moreover it is evident that the NK-2 receptor subtypes in the human bronchus and guinea pig t rachea are similar to one another, but different pharmacologically fro m the NK-2 receptor found in the hamster trachea. Subtle differences a ppear to exist between human and guinea pig airway NK-2-type receptors .