Neurokinin (NK2) receptors mediate nonadrenergic noncholinergic contractile responses to electrical stimulation and resiniferatoxin in guinea pig trachea
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abstract
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 ([βAla8]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 [βAla8]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 [βAla8]NKA(4–10), yielding −log KB values of 8.4 ± 0.2 and 9.1 ± 0.2, respectively. In the presence of 1 μM atropine, 1.4 μM indomethacin, 0.2 μM timolol, and 4 μM 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 μM) or the nitric oxide synthase inhibitor L-NAME (10 μM) but was completely inhibited by tetrodotoxin (TTX) (1 μM) 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 μM). SR-48,968 (150 nM) almost completely blocked the contractile response to 1 and 10 nM resiniferatoxin. CP-99,994 (0.3 μM) was inactive when tested alone but blocked the residual response in the presence of SR-48,968. It is concluded that TTX-sensitive NANC contractions to electrical field stimulation of guinea pig trachea are mediated by neurokinins acting primarily on NK2 receptors. Resiniferatoxin produces much more profound NANC contractile responses, which are not modified by TTX and are mediated by tachykinins acting to a large degree on NK2 receptors and, to a minor degree, on NK1 receptors.Key words: NK1 and NK2 antagonists, electrical stimulation, resiniferatoxin, guinea pig trachea.
