Selective agonists for substance P and neurokinin receptors

1 The effects of a selective NK2 receptor antagonist, SR 48968, on non-adrenergic non-cholinergic (NANC) bronchoconstriction in the guinea-pig were investigated in both in vitro and in vivo studies. 2 In isolated bronchus, the electrical field stimulation (EFS, 1 Hz for 1 min)-induced NANC bronchoconstriction was inhibited by 83% after preincubation with SR 48968 (l0-7 M) for 1 h. The selective NK1 receptor antagonist, CP 96,345 (10-6 M), together with SR 48968 completely abolished the remaining EFS-evoked NANC bronchial contraction. ST 48968 (10-7 M) totally blocked the bronchial contraction caused by neurokinin A (NKA), but reduced only slightly the bronchoconstriction caused by high concentrations of substance P (SP) and did not influence the response to acetylcholine (ACh). 3 In the guinea-pig isolated perfused lung, SR 48968 (5 x I0-M) perfusion for 30 min markedly reduced, by 95% and 68% respectively, the increase in lung resistance (RL) and the decrease in dynamic compliance (CDyfl) evoked by vagal stimulation (1 Hz for 1 min). Capsaicin (10-8 M)-evoked bronchoconstriction was also significantly inhibited by SR 48968 (5 x 10-7 M). However, the same concentration of SR 48968 did not affect the release of neuropeptide calcitonin gene-related peptide (CGRP)-like immunoreactivity (LI) evoked by either vagal stimulation or capsaicin in the isolated perfused lung, suggesting no prejunctional action. SR 48968 (5 x 10-7 M) caused a parallel shift of the concentrationresponse curve to the right by a factor of 10 for the bronchoconstriction evoked by NKA (l0-9-3 x 10-7 M) in the isolated lung, while it abolished the contraction induced by the selective NK2 receptor agonist, Nle'°NKA(4-10) (10--3 x 10-7 M).

Section: Discussionmentioning

confidence: 99%

Postjunctional inhibitory effect of the NK₂ receptor antagonist, SR 48968, on sensory NANC bronchoconstriction in the guinea‐pig

Lou

Lee

Satoh

et al. 1993

“…All experiments started after a 120 min equilibration period. In a first series of experiments, three different receptorselective tachykinin antagonists, GR 71251 (NK1 receptor selective, Hagan et al, 1990;Hall & Morton, 1991) In a second series of experiments, the selectivity of antagonists was tested against circular muscle contractions produced by the NK1 receptor-selective agonist [Sari substance P sulphone (Drapeau et al, 1987) …”

Section: Circular Muscle Stripsmentioning

confidence: 99%

Tachykininergic transmission to the circular muscle of the guinea‐pig ileum: evidence for the involvement of NK₂ receptors

Barthó

Santicioli

Patacchini

et al. 1992

1 The effect of newly developed, receptor-selective tachykinin antagonists (GR 71,251 for NK1 receptors, MEN 10,376 and L 659,877 for NK2 receptors) on noncholinergic transmission to the circular muscle of the guinea-pig ileum has been investigated. 2 In circular muscle strips of the ileum, electrical field stimulation in the presence of atropine (2 jM) and apamin (0.1 jAM) evoked a complex motor response. The tonic primary contraction in this response was reduced by GR 71,251 (10 jM) and MEN 10,376 (3-10 I1M) but not by L 659,877 (up to 10 jM). The presence of apamin was necessary in this experimental arrangement to unmask an atropine-resistant primary contraction, sensitive to tachykinin antagonists. The motor response was abolished by tetrodotoxin.3 In circular strips of the ileum GR 71,251 (10 jM) inhibited the tonic contraction produced by [Sar9] substance P sulphone, a selective NK1 receptor agonist but not that produced by [,B Alal] neurokinin A (4-10), a selective NK2 receptor agonist. By contrast, MEN 10,376 antagonized the effect of the NK2 agonist while leaving the response to the NK, agonist unaffected. 4 In whole segments of the ileum, distension of the gut wall by an intraluminal balloon placed at about 1 cm from the point of recording of mechanical activity of the circular muscle produced atropinesensitive phasic contractions (ascending enteric reflex). In the presence of atropine (2 jiM), a noncholinergic response was elicited, which required larger volumes of distension that the cholinergic one. The atropine-resistant ascending enteric reflex was enhanced by apamin (0.1 j1M) and abolished by tetrodotoxin, either in the presence or absence of apamin. 5 MEN 10,376 (3-lOM) inhibited the atropine-resistant ascending enteric reflex in the presence of apamin while GR 71,251 or L 659,877 (10 lM each) were ineffective. MEN 10,376 inhibited the atropine-resistant ascending enteric reflex to a larger extent in the absence than in the presence of apamin and also slightly inhibited the ascending enteric reflex in the absence of atropine. 6 These findings provide evidence for an involvement of NK2 tachykinin receptors in excitatory transmission to the circular muscle of the guinea-pig ileum. NK2 receptors are also involved in the physiological-like circular muscle activation produced by stimulation of intramural neuronal pathways which subserve the atropine-resistant ascending enteric reflex.

“…izing TK receptors which mediate a particular response has been greatly facilitated by the development of synthetic TK analogues which possess strong or even absolute selectivity for one particular TK receptor Drapeau et al, 1987;Regoli et al, 1988;Rovero et al, 1989). These synthetic analogues have been fruitfully employed to characterize specific TK receptors in various bioassays (Giuliani et al, 1988;Devillier et al, 1988;Maggi et al, 1989a,b,c;Patacchini et al, 1989).…”

Section: Introductionmentioning

confidence: 99%

NK₁‐receptors mediate the proliferative response of human fibroblasts to tachykinins

Ziche¹,

Morbidelli

Pacini

et al. 1990

102

1The effect of synthetic tachykinin selective receptor agonists was studied on the growth of cultured human skin fibroblasts (HF). 2 Human fibroblasts were grown in serum-free conditions in the presence of natural tachykinins (substance P and neurokinin A) and of three synthetic agonists, [fl-Ala4, Sar9, Met (02) Cell proliferation was measured by percentage increase in cell number and by [3H]-thymidine uptake following 48 h exposure to agents compared to baseline condition. 3 Neurokinin A (NKA) and substance P (SP) significantly increased cell proliferation the threshold concentrations being 10-12 and 10-11 M, respectively. Addition of thiorphan to culture conditions enhanced the effect of SP but not of NKA.4 The selective NK1-receptor agonist produced a dose-dependent increase in cell proliferation as judged by total cell number and [3H]-thymidine uptake. No significant effect was observed with NK2-and NK3-receptor agonists. 5 These data indicate that the effect of SP on fibroblast proliferation is mediated by interaction with a NK1-receptor type and local metabolism can interfere with the full expression of this effect of SP on cell proliferation.