UNIPROT:P20366 - FACTA Search

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Query: UNIPROT:P20366 (substance P)
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We have studied the effect of a novel tachykinin, neuropeptide gamma (NP gamma) on small intestinal motility in the rat. Experiments were done in vitro on longitudinal muscle strips of duodenum, and in vivo on the migrating myoelectric complex (MMC) of the small intestine. In vitro, contractile effects of NP gamma were compared with those of a selective neurokinin 1 (NK1) receptor agonist, substance P methyl ester (SPME), and a selective neurokinin 2 (NK2) receptor agonist, Nle10-NKA(4-10)(NleNKA). NP gamma, SPME and NleNKA caused concentration-dependent contractions (P < 0.001). NP gamma was eight-fold more potent than NleNKA, and 118-fold more potent than SPME. Contractile responses to NP gamma were reduced by hexamethonium (P < 0.01) and atropine (P < 0.05). The non-selective NK receptor antagonist spantide I only slightly reduced the contractile response to NP gamma, as did the selective NK1 antagonist GR 82,334, and the selective NK2 antagonist L-659,877 and MEN 10,376. In vivo, effects of NP gamma on the MMC were compared with those of the natural tachykinins substance P (SP) and neurokinin A (NKA). NP gamma disrupted the MMC and induced irregular spiking in a dose-dependent manner from 25 to 100 pmol kg-1 min-1 i.v. (P < 0.05). The effect of NP gamma was more prominent than that of NKA at equal doses, while SP had no effect. Our findings show that NP gamma exerts potent stimulatory effects on small intestinal motility, most likely mediated directly via distinct NK receptors on smooth muscle cells, but also indirectly via a cholinergic link.
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PMID:Intestinal motility responses to neuropeptide gamma in vitro and in vivo in the rat: comparison with neurokinin 1 and neurokinin 2 receptor agonists. 797 23

We describe the in vitro and in vivo pharmacological properties of MEN 10,627 or cyclo(Met-Asp-Trp-Phe-Dap-Leu)cyclo(2 beta-5 beta), the first example of a polycyclic peptide tachykinin NK2 receptor antagonist. MEN 10,627 is endowed with high affinity for NK2 receptor expressed in various species with pKB values ranging between 10.1 (hamster trachea) and 8.1 (rabbit pulmonary artery). The antagonism is of competitive type in both functional and radioligand binding assays. A 100- to 10,000-fold selectivity was found vs. NK1 or NK3 receptors expressed in various species. As an NK2 receptor antagonist, MEN 10,627 is 10- to 100-fold more potent than the monocyclic peptide antagonist L 659,877 or cyclo(Met-Gln-Trp-Phe-Gly-Leu). At the hamster NK2 receptor, MEN 10,627 is about 30-fold more potent than the nonpeptide NK2 receptor antagonist SR 48,968 [(S)-N-methyl-N[4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl) butyl]benzamide], whereas the converse is true for the rabbit NK2 receptor. Furthermore, MEN 10,627 is, up to micromolar concentrations, devoid of antagonist properties toward a wide range of transmitters of both peptide and nonpeptide nature. In urethane-anesthetized rats in vivo, MEN 10,627 (10-100 nmol/kg i.v.) produced long-lasting inhibition of contraction of the urinary bladder and duodenum produced by i.v. administration of the NK2 receptor agonist [beta Ala8]NKA(4-10), without affecting the responses produced by i.v. administration of the NK1 receptor agonist [Sar9]SP sulfone or acetylcholine. In anesthetized rats, both MEN 10,627 and SR 48,968 blocked urinary bladder contraction induced by the NK2 receptor agonist after intravenous, intranasal or intraduodenal administration. Equieffective doses of MEN 10,627 producing about 50% inhibition of the response to [beta Ala8]NKA(4-10) in the rat urinary bladder in vivo, were 0.01, 0.03 and 3 mumol/kg after intravenous, intranasal and intraduodenal administration, respectively. The corresponding doses of SR 48,968 were 0.03, 0.1 and 1 mumol/kg, after intravenous, intranasal and intraduodenal administration, respectively. In conclusion, MEN 10,627 is a potent and selective NK2 receptor antagonist, endowed with high potency and long duration of action in vivo, which is not restricted to parenteral administration.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:MEN 10,627, a novel polycyclic peptide antagonist of tachykinin NK2 receptors. 799 62

1. The aim of this study was to characterize the tachykinin NK2 receptor subtype mediating the spasmogenic response in the human isolated bronchus. The motor response to neurokinin A (NKA) and the selective NK2 agonist [beta Ala8]NKA(4-10), as well as the antagonistic effects of cyclic (L659,877) and linear (MEN 10376) peptide NK2 antagonists were assessed in the presence or absence of amastatin (an inhibitor of aminopeptidases A and M). 2. NKA was more potent than [beta Ala8]NKA(4-10) in eliciting bronchoconstriction (pD2 being 7,43 and 6,87 respectively). In the presence of amastatin (1 microM), the estimated affinity of [beta Ala8]NKA(4-10), but not that of NKA, was significantly increased to yield a pD2 of 7,44. 3. L659,877 and MEN 10376 inhibited [beta Ala8]NKA(4-10)-induced contraction with similar affinities; pA2 values were 5.7 +/- 0.22 and 6.3 +/- 0.32, respectively. Amastatin (1 microM) increased the potency of MEN 10376 to 7.28 +/- 0.46, whereas that of L659,877 was unaffected. 4. In the presence of amastatin the pseudopeptide MDL 28,564 behaved as a partial agonist. 5. We conclude that the NK2 receptor subtype present in the human bronchus has properties similar to those described for the circular muscle of the human colon and thus may be classified as a 'NK2A' subtype. We show that the apparent potency of peptides, bearing N-terminal acidic residues, is influenced by an amastatin-sensitive peptidase, possibly aminopeptidase A.
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PMID:Characterization of the tachykinin NK2 receptor in the human bronchus: influence of amastatin-sensitive metabolic pathways. 800

1. The aim of this study was to investigate the effect of various antagonists, selective for the tachykinin NK1 or NK2 receptor, on the atropine-resistant ascending excitatory reflex (AER) to the circular muscle of the guinea-pig ileum elicited by radial stretch (balloon distension) or electrical field stimulation. 2. Submaximal and maximal atropine- (1 microM) resistant AER elicited by balloon distension averaged about 40-50% and 70-90% of maximal circular spasm to 80 mM KCl, respectively. The NK1 receptor antagonist, (+/)-CP 96,345 (1 microM) inhibited both maximal and submaximal AER. FK 888 (1-3 microM) inhibited submaximal AER only. RP 67,580 (1 microM) was ineffective. The NK2 receptor antagonist, GR 94,800, inhibited both maximal and submaximal AER at all concentrations tested (0.1-3.0 microM), while SR 48,968 was effective only at 1.0 microM. The NK2 receptor antagonists, MEN 10,376 and MEN 10,573 inhibited both submaximal and maximal AER at 10 and 1.0 microM, respectively. 3. In other experiments, an NK1 receptor antagonist, (+/-)-CP 96,345 or FK 888 (1.0 microM in each case) was administered first and the effect of GR 94,800 (1.0 microM) on the residual AER response was determined; or GR 94,800 was administered first and the effect of (+/-)-CP 96,345 or FK 888 was determined. The results of these experiments indicated an additive effect produced by the combined treatment with NK1 and NK2 receptor antagonists. 4. Electrical field stimulation (10 Hz for 0.5 s, 10-20 V, 0.15-0.3 ms pulse width) with electrodes placed at 1.4-1.8 cm anal to the recording site, produced ascending contractions which were almost abolished by 10 MicroM hexamethonium (electrically-evoked AER). In the presence of apamin (0.1 MicroM) and N0-nitro-L-arginine (30 MicroM) these contractions were reproducible over 10 consecutive stimulation cycles.GR 94,800 (1 MicroM) and FK 888 (1 MicroM) both produced a partial inhibition of the electrically-evoked AER and their combined administration produced an inhibitory effect which was larger than that induced by each antagonist alone.5. FK 888 (1-3 MicroM), GR 94,800 (1-3 MicroM), MEN 10,573 (1 MicroM) and MEN 10,376 (10 MicroM) did not significantly affect the atropine-sensitive twitch contractions produced by electrical field stimulation of the guinea-pig ileum longitudinal muscle-myenteric plexus preparation, which were abolished by 10-30 MicroM procaine, 1 MicroM tetrodotoxin or 1 MicroM atropine. (+/-)-CP 96,345 (1 MicroM) and SR 48,968 (1 ILM)produced 12% and 27% inhibition of cholinergic twitches in the longitudinal muscle of the ileum,respectively.6. We conclude that both NK1 and NK2 receptors mediate the atropine-resistant AER to the circular muscle of the ileum. NK2 receptor activation plays a more important role than NK1 receptor activation in the AER evoked by radial stretch. Since a consistent fraction of the distension- and electrically evoked atropine-resistant AER persists in the presence of combined NK1 and NK2 receptor blockade,the existence of a third excitatory transmitter to the circular muscle of the ileum, in addition to acetylcholine and tachykinins, is suggested.
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PMID:Tachykinin NK1 and NK2 receptor antagonists and atropine-resistant ascending excitatory reflex to the circular muscle of the guinea-pig ileum. 803 37

Receptors for tachykinins and the signaling pathway to which they are coupled were characterized in dispersed muscle cells from the longitudinal muscle layer of the rat intestine. A technique of receptor protection whereby selective agonists and antagonists were used to protect one receptor while other receptors were inactivated with N-ethylmaleimide enabled each tachykinin receptor type to be identified separately. Protection of neurokinin (NK)-1 receptors with the selective NK-1 agonist, substance P methylester, or antagonist, GR-82,334 (Glp-Ala-Asp-Pro-Asn-Lys-Phe-Tyr-D-Pro[spiro-gamma-lactam]Leu-Trp-NH2), preserved the contractile response and increase in cytosolic-free Ca++ ([Ca++]i) induced by substance P methylester only; protection of NK-2 receptors with the selective NK-2 agonist, beta-[Ala8]NKA(4-10), or the selective NK-2b antagonist, L-659,877 [cyclo(Leu-Met-Gln-Trp-Phe-Gly)], preserved the contractile response and increase in [Ca++]i induced by beta-[Ala8]NKA(4-10) only; and protection of NK-3 receptors with the selective NK-3 agonist, senktide succinyl-[Asp6,MePhe8]substance P(6-11), preserved the contractile response and increase in [Ca++]i induced by succinyl-[Asp6,MePhe8]substance P(6-11) only. When used as a protective agent, the NK-2a antagonist, MEN-10,376 (H-Asp-Tyr-D-Trp-Val-D-Trp-D-Trp-Lys-NH2), did not preserve the response to any tachykinin agonist. Protection of NK-1, NK-2 and NK-3 receptors preserved fully the responses to the preferential endogenous agonists, substance P, NKA and NKB, respectively, but they also preserved in part (30-40%) the responses to the nonpreferential agonists. Because substance P and NKA are coreleased from the same precursor in intestinal muscle tissue, the pattern implied the existence of considerable spareness in the contractile response of muscle cells to tachykinins. Studies on dispersed circular muscle cells using selective tachykinin agonists as protective agents confirmed the presence of three tachykinin receptor types. The results demonstrate the coexistence of NK-1, NK-2b and NK-3 receptors on muscle cells of rat intestine that are preferentially activated by substance P, NKA and NKB, respectively, and are coupled separately to one signaling pathway mediating contraction.
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PMID:Coexistence of three tachykinin receptors coupled to Ca++ signaling pathways in intestinal muscle cells. 803 20

The possible involvement of tachykinin neurokinin-1 and neurokinin-2 receptors in the activation of various micturition-related reflexes was assessed by the intrathecal administration of selective neurokinin-1 or neurokinin-2 receptor antagonists at lumbosacral spinal cord level in urethane-anaesthetized rats. The effect of the glutamate N-methyl-D-aspartate receptor antagonist, 2-amino-5-phosphonovaleric acid, was also investigated for comparison. The effect of antagonists was investigated on: (i) the chemonociceptive vesicovesical reflex activated by topical application of capsaicin onto the urinary bladder; (ii) the distension-induced micturition reflex produced by transvesical filling with saline; (iii) distension-induced rhythmic bladder contractions in isovolumetric conditions (urethra-ligated rats); and (iv) the somatovesical excitatory reflex caused by noxious perineal pinching. The neurokinin-2 receptor selective antagonists MEN 10,376 and SR 48,968 were ineffective in the three models in all doses tested. Selective neurokinin-1 receptor antagonists blocked the chemonociceptive reflex produced by topical application of capsaicin with the rank order of potency (lowest effective dose in brackets): GR 82,334 (1 nmol/rat) > RP 67,580 (10 nmol/rat) > (+/-)CP 96,345 (100 nmol/rat). Unlike GR 82,334, RP 67,580 (10 nmol/rat) and (+/-)CP 96,345 (100 nmol/rat) were also effective on the distension-induced micturition reflex elicited by transvesical filling. Similarly, distension-induced rhythmic contractions were inhibited by RP 67,580 (10 nmol/rat) and (+/-)CP 96,345 (100 nmol/rat) whereas the effect of GR 82,334 was not significant. RP 68,651, the enantiomer of RP 67,580 devoid of neurokinin-1 receptor blocking activity, was inactive in both models. 2-Amino-5-phosphonovateric acid (250 nmol/rat) blocked the three types of vesicoexcitatory reflexes. Intravenous administration of (+/-)CP 96,345, RP 67,580 or 2-amino-5-phosphonovateric acid at the same doses proven effective after the intrathecal route, had no effect on distension-induced rhythmic contractions. To ascertain whether the effect of neurokinin-1 receptor antagonists or 2-amino-5-phosphonovaleric acid may be related to a blockade of tachykinins released from capsaicin-sensitive primary afferent neurons, the effect of RP 67,580 was investigated on the distension-evoked micturition reflex in capsaicin-pretreated rats. Capsaicin pretreatment (50 mg/kg, subcutaneously, four days before) increased bladder capacity. RP 67,580 was no longer effective in capsaicin-pretreated rats. In contrast, 2-amino-5-phosphonovateric acid produced a further increase in bladder capacity in capsaicin-pretreated rats. We conclude that tachykinin neurokinin-1 but not neurokinin-2 receptors are involved in the activation of vesicoexcitatory micturition-related reflexes in the rat spinal cord.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Evidence for a role of tachykinins as sensory transmitters in the activation of micturition reflex. 810 62

The effects of intrathecally (i.t.) injected selective tachykinin NK2 receptor antagonists, MEN 10,207, MEN 10,376 and R396, on the spinal effect of neurokinin A were studied in decerebrate, spinalized, unanesthetized rats. I.t. neurokinin A (7 pmol) briefly facilitated the flexor reflex, an effect that was dose dependently inhibited by pretreatment with MEN 10,207 and MEN 10,376 with similar and high potency. I.t. R396 itself caused strong facilitation of the flexor reflect. At lower doses, the effect of i.t. neurokinin A was potentiated by R396. R396 only exhibited moderate antagonism of neurokinin A-induced reflex facilitation even at very high doses. It has been proposed that the tachykinin NK2 receptor may be further classified into two subtypes, NK2A and NK2B, with MEN 10,207 and MEN 10,376 having high affinity for the former and R396 for the latter. Our results suggested that the tachykinin NK2 receptor in rat spinal cord which mediates the excitatory effect of neurokinin A may belong to the NK2A subpopulation of receptors.
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PMID:Differential effects of selective tachykinin NK2 receptor antagonists in rat spinal cord. 813 76

It is known that tachykinins (substance P, neurokinin A) participate in the excitatory neural pathways subserving peristaltic motor activity in the intestine. The aim of the present study was to elucidate the types of tachykinin receptor (NK-1 or NK-2) involved in peristalsis by the use of receptor subtype-selective antagonists. Peristaltic motility in isolated segments of the guinea-pig ileum was induced by pumping fluid into the oral end of the intestinal segment. By way of the intraluminal pressure the compliance of the intestinal wall during the preparatory phase and the pressure threshold to trigger the emptying phase of peristalsis were recorded. The tachykinin antagonists were used at concentrations that were at least 30 times in excess of the equilibrium dissociation constants which had previously been evaluated with receptor subtype-selective agonists on the guinea-pig ileum circular muscle. The NK-1 selective antagonist CP-96,345 (0.3 microM) had a slight stimulant influence on peristalsis, whereas the NK-2 selective antagonists MEN-10,376 (10 microM), GR-94,800 (0.3 microM) and SR-48,968 (0.1 microM) led to a small inhibition of motor activity. However, when given after exposure of the ileum to a threshold concentration of atropine (5-20 nM) causing little depression of peristalsis, the tachykinin NK-2 receptor antagonists invariably abolished peristalsis. This synergistic interaction was not seen when SR-48,968 was administered after the ileal segments had been exposed to concentrations of hexamethonium, isoproterenol or calcitonin gene-related peptide that by themselves caused a slight inhibition of peristalsis only.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Synergistic role of muscarinic acetylcholine and tachykinin NK-2 receptors in intestinal peristalsis. 817 May 3

We have examined the effect of various natural and synthetic tachykinins on the steady state Ca(++)-rise ([Ca++]i) in transfected chinese hamster ovary cells expressing recombinant human Neurokinin 2 (NK2) receptors. The rank order of potency with natural tachykinins was NeurokininA > Neurokinin B > Eledoisin > Physaelamin > substance P. The selective NK2 agonist, [beta-Ala8]NKA(4-10) was very potent, with an EC50 value of 4.83 x 10(-9) M whereas Senktide, MePhe7NKB and Sar9, (MetO2)11 substance P, selective NK3 and NK1 agonists, respectively, did not have any effect on [Ca++]i in hrNK2CHO cells, suggesting a selective and preferential recognition and activation of NK2 receptors in these cells. (+/-) SR 48968, a selective NK2 antagonist, abolished the beta-AlaNKA-induced [Ca++]i with an IC50 value of 0.7 nM. Two other peptidic NK2 antagonists, MEN 10376 and L-658977, were less active with IC50 values of 49 nM and 5.29 microM, respectively. In contrast, (+/-) CP-96,345 and (+/-)CP-99,994 and RP 67580, all selective NK1 antagonists, did not have any effect on the beta-AlaNKA-induced [Ca++]i in hrNK2CHO cells (+/-) SR 140333, a potent and selective NK1 antagonist, had a 35% inhibition under similar conditions. These data demonstrate a high selectivity and sensitivity to NK2 receptor mediated [Ca++]i in rhNK2R-CHO cells and may be of value as a rapid, selective test of drug action at the human NK2 receptors in vitro.
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PMID:Pharmacological characterization of tachykinin-induced intracellular calcium rise in a human NK2 receptor transfected cell line. 818 7

The activity and selectivity of MEN 10,573 and MEN 10,612, novel cyclic pseudopeptides which are selective tachykinin NK-2 receptor antagonists is described, as compared to that of previously characterized linear and cyclic compounds. For the NK-2 receptor, the activity of test compounds was investigated in the hamster isolated trachea (HT) and the endothelium-deprived rabbit isolated pulmonary artery (RPA), two preparations which are endowed with pharmacologically distinct forms of the NK-2 receptor. The novel cyclic pseudopeptides, MEN 10,573 and MEN 10,612 displayed very high affinity for the NK-2 receptor in the HT (pA2 8.66 and 9.06, respectively) which is higher than that observed in the RPA (pA2 7.31 and 7.41 for MEN 10,573 and MEN 10,612, respectively). The antagonism exerted by MEN 10,573 and MEN 10,612 was of competitive nature in both preparations. MEN 10,573 and MEN 10,612 also displayed competitive antagonism for NK-2 receptor-mediated responses in the rabbit bronchus (RB), rat vas deferens (RVD), circular muscle of the human colon (HUC) and ileum (HUI). In the RB, HUC and HUI, the potency of the novel cyclic pseudopeptides was comparable to that of MDL 29,913 and about 10-fold greater than that of L659,877. In the RVD however, the potency of MEN 10,573 MEN 10,612 or MDL 29,913 was similar to that of L659,877. In anaesthetized rats, i.v. injection of MEN 10,612 produced a selective and long-lasting blockade of the urinary bladder contraction produced by the i.v. injection of the NK-2 receptor selective agonist [beta Ala8]neurokinin A(4-10), without affecting the response to the NK-1 receptor selective agonist [Sar9]substance P sulfone.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:MEN 10,573 and MEN 10,612, novel cyclic pseudopeptides which are potent tachykinin NK-2 receptor antagonists. 823 1

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