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)-1 (Ac-[Arg6,Sar9,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 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, [beta-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 [beta-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-a zab icyclo- [2.2.2]octan-3-amine (CP 96,345) was without effect on contractile responses to [beta-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.(ABSTRACT TRUNCATED AT 250 WORDS)
Ellis
J L
JL
Johns Hopkins Asthma and Allergy Center, Baltimore, Maryland.
Undem
B J
BJ
Kays
J S
JS
Ghanekar
S V
SV
Barthlow
H G
HG
Buckner
C K
CK
D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D001980:Bronchi / Q000502:physiology*; D006224:Cricetinae; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D018039:Receptors, Tachykinin / Q000187:drug effects*; D013045:Species Specificity; D015320:Tachykinins / Q000494:pharmacology*; D014132:Trachea / Q000502:physiology*
D018039:Receptors, Tachykinin; D015320:Tachykinins