Neurokinin (NK2) receptors mediate nonadrenergic noncholinergic contractile responses to electrical stimulation and resiniferatoxin in guinea pig trachea.
In the present study we characterized the receptor(s) that mediates non-adrenergic non-cholinergic (NANC) contractions of isolated guinea pig cervical trachea, using CP-99,994, a selective neurokinin (NK1) receptor antagonist, and SR-48,968, a selective neurokinin (NK2) receptor antagonist. The activity of these two antagonists was determined against contractions to the selective agonists ([beta Ala8]NKA(4-10) for NK2 and [Sar9,Met(O2)11]SP for NK1) and the nonselective (SP and NKA) NK receptor agonists. CP-99,994 was inactive versus NKA and [beta Ala8]NKA(4-10) but antagonized SP- and [Sar9,Met(O2)11]SP-induced contractions with -log KB values of 5.6 +/- 0.2 and 7.7 +/- 0.2, respectively. SR-48,968 was inactive versus SP and [Sar9,Met(O2)11]SP but was active versus NKA and [beta Ala8]NKA(4-10), yielding -log KB values of 8.4 +/- 0.2 and 9.1 +/- 0.2, respectively. In the presence of 1 microM atropine, 1.4 microM indomethacin, 0.2 microM timolol, and 4 microM thiorphan, electrical field stimulation (16 Hz, 2.0 ms, 50 V for 10 every 30 min) elicited a NANC contractile response which was not significantly altered by CP-99,994 (3 microM) or the nitric oxide synthase inhibitor L-NAME (10 microM) but was completely inhibited by tetrodotoxin (TTX) (1 microM) and was also reduced to 58 +/- 12, 31 +/- 16, 8 +/- 4, and 0% of control by 15, 50, 150, and 1500 nM SR-48,968, respectively. Resiniferatoxin (1 and 10 nM) produced a well-maintained concentration-dependent contraction, which was 57.8 +/- 4.8 and 61.6 +/- 3.8%, respectively, of the carbachol-induced maximum response. Contractions were not significantly modified by L-NAME and were not blocked by TTX (1 microM).(ABSTRACT TRUNCATED AT 250 WORDS)
Charette
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Merck Frosst Centre for Therapeutic Research, Pointe Claire-Dorval, PQ, Canada.
Foulon
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Rodger
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Jones
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D000403:Airway Resistance / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D004224:Diterpenes / Q000494:pharmacology*; D004558:Electric Stimulation; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D019331:NG-Nitroarginine Methyl Ester; D009498:Neurotoxins / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D018040:Receptors, Neurokinin-1 / Q000187:drug effects / Q000502:physiology; D018041:Receptors, Neurokinin-2 / Q000187:drug effects / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects / Q000294:innervation / Q000502:physiology
D001549:Benzamides; D004224:Diterpenes; D009498:Neurotoxins; D010880:Piperidines; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine; D013779:Tetrodotoxin; C073839:SR 48968; D001120:Arginine; C024353:resiniferatoxin; D019331:NG-Nitroarginine Methyl Ester