Pharmacological examination of receptors mediating contractile responses to tachykinins in airways isolated from human, guinea pig and hamster

J. L. Ellis, Bradley J Undem, J. S. Kays, S. V. Ghanekar, H. G. Barthlow, C. K. Buckner

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Abstract

The abilities of agonists selective for neurokinin (NK)-1 (Ac- [Arg6,Sar9,Met(O2)11]-SP6-11,ASMSP), NK-2 ([β-Ala8]-NKA4-10) and NK-3 ([Asp5,6,MePhe8]-SP5-11, senktide analog) receptors to contract human bronchus and guinea pig and hamster trachea were studied. The antagonism of these responses by selective antagonists was also examined. In the human bronchus and hamster trachea, [β-Ala8]-NKA4-10 was the most potent agonist, whereas ASMSP and senktide analog failed to elicit contractions greater than 50% of the maximum response even at concentrations reaching 1 to 3 x 10-4 M. By contrast, both ASMSP and [β-Ala8]-NKA4-10 were potent contractile agonists in guinea pig trachea. In all tissues, the selective NK-1 receptor antagonist (2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)-methyl]-1- azabicyclo-[2.2.2]octan-3-amine (CP 96,345) was without effect on contractile responses to [β-Ala8]-NKA4-10. Blockade by CP 96,345 of responses to ASMSP was, however, observed in the guinea pig trachea, but not in human bronchus or hamster trachea. Responses to ASMSP in human bronchus 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 inhibited by NK-2 antagonists. The NK-2 selective antagonists Ac-Leu-Asp-Gly-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 [β-Ala8]-NKA4-10 in human bronchus, guinea pig trachea and hamster trachea. The rank order of potency in human bronchus was SR 48,968 > MEN 10,376 ≥ R 396. A similar order was obtained in 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 contractions of human bronchus and hamster trachea are mediated by only NK-2-type receptors, whereas contractions of the guinea pig trachea involve activation 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 trachea are similar to one another, but different pharmacologically from the NK-2 receptor found in the hamster trachea. Subtle differences appear to exist between human and guinea pig airway NK-2-type receptors.

Original languageEnglish (US)
Pages (from-to)95-101
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume267
Issue number1
Publication statusPublished - 1993

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ASJC Scopus subject areas

  • Pharmacology

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