Incubation of proximal segments of the rat isolated duodenum with NG‐nitro‐L‐arginine (L‐NOARG; 3–100 μm) produced a concentration‐dependent increase in both resting tone and the amplitude of the spontaneous contractions. These effects were attenuated by concurrent incubation with L‐arginine (1 mM) but not D‐arginine (1 mM).These changes in resting tone and motility induced by L‐NOARG (30 μm) were substantially reduced by concurrent incubation with tetrodotoxin (1 μm) or hexamethonium (10 μm), implicating the involvement of a local neuronal response.The L‐NOARG‐induced increase in duodenal motility was not, however, inhibited by atropine (1 μm), guanethidine (6.4 μm) phentolamine (1 μm), or indomethacin (10 μm), indicating a non‐cholinergic, non‐adrenergic and non‐prostanoid‐mediated contractile response.The NK1/NK2 tachykinin receptor antagonist, (D‐Pro2, D‐Trp7,9 substance P, 1–10 μm), and the NK2‐receptor antagonists, MEN 10,207 and MEN 10,376 (1–5 μm), concentration‐dependently reduced the effect of L‐NOARG (30 μm) on spontaneous duodenal motility.The resting tone and amplitude of the spontaneous contractions was likewise increased by incubation with NG‐monomethyl‐L‐arginine (L‐NMMA; 100–1000 μm). However, incubation with L‐NMMA (100 μm) attenuated the actions of more potent L‐NOARG (30 μm) on resting motility.Administration of E.coli endotoxin (3 mg kg−1, i.v.) to the rat 5 h prior to tissue removal, at a time of known induction of NO synthase, reduced the amplitude of spontaneous contractions of the isolated duodenum, an effect inhibited by pretreatment of the rats with dexamethasone (1 mg kg−1) 2 h prior to endotoxin challenge.These findings indicate a role of endogenous NO in the modulation of spontaneous tone and motility in the rat duodenum. Induction of NO synthase may result in a reduction in spontaneous motility of the tissue. By contrast, inhibition of constitutive NO biosynthesis unmasks a contractile response that is neuronally mediated and involves tachykinin NK2 receptors.

1996-01-01·The Journal of pharmacology and experimental therapeutics

VALENTIN PARNAKH, APOSTLE OF ECCENTRIC DANCE

Article

作者: Burcher, E ; Stamatakos, C ; Mussap, C J

Tachykinin receptors in the dog bladder were characterized using radioligand binding, functional and autoradiographic techniques. In detrusor muscle homogenates, specific binding of [125l]iodohistidyl neurokinin A (INKA) and [125l]Bolton Hunter eledoisin was reversible, saturable and, to a single class of sites of Kd, 3,6 and 27 nM, respectively. No specific binding of [125l]Bolton Hunter[Sar9, Met (O2)11] substance P occurred. INKA binding was reduced by the peptidase inhibitor bacitracin. The rank potency order of agonists competing for binding of both radioligands indicated interaction at NK-2 sites. NK-2-selective antagonists also competed for INKA binding, with SR 48968, GR 94800, MDL 29913 and the selective agonist [Lys5, MeLeu9, Nle10]-NKA(4-10) showing biphasic binding profiles. Autoradiographic studies revealed specific binding of INKA and [125l]Bolton Hunter eledoisin over detrusor muscle and small arteries. [125l]Bolton Hunter [Sar9, Met (O2)11] SP labeled the intima of arteries and arterioles, but not the detrusor muscle. Tachykinins contracted detrusor muscle strips, with potency order at the carbachol EC15 NKA = kassinin > [Lys5, MeLeu9, Nle10]-NKA(4-10) = neuropeptide gamma = neuropeptide K = NKB > > MDL 28564, with [Sar9, Met(O2)11]-SP ineffective. Shallow concentration-response curves, variable efficacies and inhibition by atropine and mepyramine suggest that other mechanisms may influence contractile responses. Responses to [Lys5, MeLeu9, Nle10]-NKA(4-10) were inhibited competitively by MDL 29913 and MEN 10207 (pA2 values: 6.4 and 5.3, respectively). Antagonism by SR 48968 and GR 94800 was noncompetitive (both pK8 values 8.9). In summary, NK-2-preferring ligands showed superior potency as both binding competitors and contractile agonists, demonstrating that NK-2 receptors mediate detrusor muscle contraction, similar to the human detrusor. Tachykinins may play important roles in the micturition reflex and in regulating detrusor muscle blood flow in the dog.

1995-11-01·Neuropeptides3区 · 医学

Further evidence that tachykinin-induced contraction of human isolated bronchus is mediated only by NK2-receptors

3区 · 医学

Article

作者: H Magnussen ; K.F Rabe ; R.L.G Sheldrick ; A Fischer ; R.A Coleman

The tachykinin-receptors mediating contraction of human bronchus have been characterized using both tachykinin-receptor selective agonists and blocking drugs under conditions where tachykinin metabolism by endogenous peptidases has been controlled, and true equilibrium conditions have been established. The findings that neurokinin A (EC50 = 2 nM) is the most potent agonist, and the NK2-receptor selective agonist, GR64349, is only 3-fold weaker, whereas agonists selective for NK1-receptors, substance P methyl ester, or NK3-receptors, senktide, are inactive, suggest that this effect is mediated exclusively by NK2-receptors. This is supported by observations that GR64349 is antagonised by the selective NK2-receptor blocking drugs, MEN10207 (pA2 = 6.7), R396 (pA2 = 6.1), (+/-)SR48968 (pA2 = 8.4) and GR159897 (pA2 = 8.6), but not by the NK1-receptor blocking drug, GR82334 (pA2 < 5). In approximately half of the preparations, the peptidase inhibitors, phosphoramidon (1 microM) and bestatin (100 microM), caused a marked and well-maintained contraction (approximately 20% of neurokinin A maximum), which may indicate a role for endogenous tachykinins in the regulation of tone in this preparation. This is supported by the finding that neurokinin A-immunoreactive nerve fibres are located around intrinsic neurones of local ganglia and within the smooth muscle layer of this preparation.

100 项与 MEN-10207 相关的药物交易

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