Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The contractile effect of substance P, neurokinin A, receptor selective agonists for tachykinin receptors and NK2 tachykinin receptor antagonists was investigated in mucosa-free circular strips of the human isolated colon. Neurokinin A and substance P produced concentration-dependent contractions which approached 80-90% of the maximal response to carbachol. Neurokinin A was about 370 times more potent than substance P. The action of neurokinin A and substance P was not modified by peptidase inhibitors (bestatin, captopril and thiorphan, 1 microM each). The NK2 receptor selective agonist, [beta-Ala8]neurokinin A-(4-10) closely mimicked the response to neurokinin A while NK1 and NK3 receptor selective agonists were active only at microM concentrations. The pseudopeptide, MDL 28,564, which is one of the most selective NK2 ligands available, behaved as a full agonist. Responses to [beta-Ala8]neurokinin A were antagonized by NK2 receptor selective antagonists, with the rank order of potency MEN 10,376 greater than L 659,877 much greater than R 396. These data indicate that NK2 tachykinin receptors play a dominant role in determining the contraction of the circular muscle of the human colon to peptides of this family. The NK2 receptor subtype responsible for this effect belongs to the same subtype (NK2A) previously identified in the rabbit pulmonary artery and guinea-pig bronchi.
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PMID:NK2 tachykinin receptors and contraction of circular muscle of the human colon: characterization of the NK2 receptor subtype. 172 45

1. We have investigated the ability of prostacyclin (PGI2) to contract guinea-pig isolated bronchi and the possible involvement of capsaicin-sensitive primary afferents in the response to PGI2. 2. PGI2 (0.1-100 microM) produced concentration-dependent contractions of the guinea-pig isolated bronchi. In vitro capsaicin desensitization (10 microM for 30 min followed by washing) significantly reduced the PGI2-induced contraction at all concentrations tested. A capsaicin-resistant component of contraction (40-60% of the overall response) was also evident. 3. Ruthenium red (3 microM), an inorganic dye which acts as a selective functional antagonist of capsaicin, significantly decreased PGI2-induced contractions, without affecting the response to substance P, neurokinin A or acetylcholine. 4. MEN 10, 207, (Tyr5, D-Trp6,8,9, Arg10)-neurokinin A (4-10) (3 microM), a selective antagonist of NK2-tachykinin receptors, significantly decreased PGI2-induced contractions and neurokinin A-induced contractions, without affecting the response to acetylcholine. 5. The effect of ruthenium red and MEN 10,207 on the one hand, and that of ruthenium red and capsaicin on the other was non additive. 6. These results indicate that PGI2-induced contraction of the guinea-pig isolated bronchi involves two distinct mechanisms, one of which involves transmitter (tachykinins) release from peripheral endings of capsaicin-sensitive primary afferents. In as much as PGI2-activation of primary afferents is sensitive to ruthenium red, we suggest that PGI2 shares a common mechanism of tachykinin release with that activated by capsaicin.
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PMID:Prostacyclin activates tachykinin release from capsaicin-sensitive afferents in guinea-pig bronchi through a ruthenium red-sensitive pathway. 172 16

During the preparation of the NK-2 selective tachykinin antagonist MEN 10208 (Thr-Asp-Tyr-D-Trp-Val-D-Trp-D-Trp-Arg-NH2) and its analogs by the solid-phase method employing the Boc strategy routinely used in our laboratory, we encountered difficulties in the coupling of hydrophobic amino acids D-Trp and Val. To study the coupling problems several syntheses of MEN 10208 and analogs were carried out with different activation strategies. These syntheses yielded considerable amounts of deletion sequences even though a negative Kaiser test was obtained after each coupling. Inaccessibility of the free amino group of the growing peptide due to steric hindrance of the hydrophobic residues during coupling, and for the ninhydrin complex during the Kaiser test, may account, at least in part, for the unsatisfactory synthetics results and for the false-negative ninhydrin tests. Repetition of each synthesis with the Fmoc strategy on a newly developed DOD resin for peptide amides using the DCC/HOBt chemistry gave superior results in terms of the yield and purity of the crude peptides. Therefore, the Fmoc strategy appears to offer advantages over the Boc method for the preparation of these peptides containing hydrophobic amino acids.
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PMID:Solid-phase synthesis of neurokinin A antagonists. Comparison of the Boc and Fmoc methods. 185 Mar 90

The present study was designed to evaluate the simultaneous presence of epinephrine (E), norepinephrine (NE), met-enkephalin (ME)-, somatostatin (SRIF)- and substance P (SP)- like immunoreactivities (LI) in extracts of 12 pheochromocytomas obtained at the time of surgery from 10 patients. Moreover, catecholamines and ME-LI levels were measured in peripheral plasma of each patient. Each pheochromocytoma was characterized by a high variability of ME-LI, SRIF-LI, SP-LI, E and NE levels. The highest E concentrations were found in tumors from patients with Multiple Endocrine Adenomatosis (MEA) IIa syndrome, whereas in sporadic pheochromocytomas NE was the main catecholamine. Among the neuropeptides ME-LI showed the highest intratumoral concentration, and SP-LI the lowest. No correlations were found between intratumoral levels of catecholamines and any of the neuropeptides or between any of the different neuropeptides measured. Plasma catecholamine levels were not correlated with intratumoral catecholamine levels. Plasma ME-LI was higher than normal in only one patient. No correlation was observed between tumoral CA or peptide content and the clinical picture. Our study confirms that human pheochromocytoma cells can synthetize different neuropeptides. The variability of the clinical picture very likely depends on the biochemical and biological heterogeneity of this chromaffin tumor.
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PMID:Measurement of catecholamines, met-enkephalin, somatostatin and substance P-like immunoreactivities in 12 human pheochromocytomas. 245 81

1. Intrathecal (i.t.) injections of the (tachykinin) NK1 receptor agonist, substance P methyl ester (SPME; 20 pmol), or the NK2 receptor agonist, neurokinin A (NKA; 20 pmol), substantially decreased the cutaneous mechanical threshold and markedly enhanced the touch-evoked response of posterior biceps femoris-semitendinosus (PBF-ST) spinal flexor motoneurones in decerebrate-spinal rats. This cutaneous mechanical reflex allodynia was prevented by pretreatment with the NK1 antagonist RP 67580 (2.28 nmol, i.t.) and the NK2 antagonist MEN 10376 (0.7 nmol, i.t.), respectively. 2. Electrical stimulation of the sural nerve at C fibre strength or cutaneous application of the irritant, mustard oil, produced prolonged cutaneous mechanical allodynia in PBF-ST motoneurones (15 min and > 1 h, respectively). Pretreatment with RP 67580 but not MEN 10376 prevented this, but when RP 67580 was administered 25 min after the application of mustard oil, the established hypersensitivity of the flexor motor reflex was not reversed. The enantiomer of RP 67580, RP 68651 was without effect. 3. Injection of bradykinin (60 microM, 80 microliters) into the gastrocnemius muscle increased the cutaneous mechanical hypersensitivity of PBF-ST flexor motoneurones for 40-50 min. MEN 10376, but not RP 67580, prevented this, but only when administered prior to the bradykinin injection. 4. These results suggest that the induction, but not the maintenance, of cutaneous mechanical allodynia in flexor motoneurones is NK receptor dependent, with cutaneous C fibre conditioning inputs acting via NK1 and muscle C fibre conditioning inputs via NK2 receptor subtypes.
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PMID:Involvement of neurokinin receptors in the induction but not the maintenance of mechanical allodynia in rat flexor motoneurones. 747 37

In vitro and in vivo test systems were used to compare the biological activities of substance P and the neurokinins A and B with those of a newly isolated substance P-like acidic peptide, PG-SPI (pGlu-Pro-Asn-Pro-Asp-Glu-Phe-Phe-Gly-Leu-Met-NH2). On nearly all the isolated smooth muscle preparations tested, PG-SPI appeared only slightly more potent than SP, but on guinea pig trachea it was 50 times more potent. The in vitro spasmogenic effect of PG-SPI on guinea pig trachea was inhibited by the NK1 receptor antagonist, CP 96,345. In in vivo tests, intracerebroventricularly injected PG-SPI was about 20 times more potent than SP in inhibiting gastric acid secretion and emptying in rats. Tests with antagonists showed that CP 96,345 reduced PG-SPI-induced inhibition of gastric emptying and the NK2 receptor antagonist, MEN 10,376, sharply blocked PG-SPI-induced inhibition of gastric acid secretion. These findings fit poorly into the current classification of tachykinin receptors and suggest that the acidic substance P-like peptide is a valuable tool for studying the functional role of other tachykinin receptor subtypes.
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PMID:Parallel bioassay of PG-SPI, an amphibian acidic SP-like peptide, mammalian basic substance P, and neurokinins A and B on in vitro and in vivo test systems. 747 92

The selective agonists of tachykinin NK1, NK2 and NK3 receptors, respectively [Pro9]substance P, [Lys5,MeLeu9,Nle10]neurokinin A-(4-10) and senktide, stimulated phosphoinositide breakdown in slices of the guinea pig ileum. This was also the case with septide which has recently been found to act on a new type of tachykinin receptors in this tissue. The NK1, NK2 and septide-evoked responses were completely antagonized in the combined presence of (+/-)-CP-96,345 and MEN 10,376 which are potent and selective antagonists of tachykinin NK1 and NK2 receptors respectively in the guinea pig ileum. Like senktide, other available NK3 receptor agonists, such as [MePhe7]neurokinin B, [MeVal7]neurokinin B, [Pro7]neurokinin B and DiMe-C7, stimulated phosphoinositide hydrolysis in either the absence or combined presence of (+/-)-CP-96,345 and MEN 10,376, although senktide was the most potent. Therefore, following the blockade of tachykinin NK1, NK2 and septide-sensitive receptors, the accumulation of inositol monophosphate appears to be a valuable, rapid and sensitive bioassay for determining the activity of NK3 receptor agonists and putative NK3 receptor antagonists.
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PMID:A new selective bioassay for tachykinin NK3 receptors based on inositol monophosphate accumulation in the guinea pig ileum. 750 59

The dogfish tachykinin peptide scyliorhinin I and a number of its analogues substituted in position 7 were tested in bioassays for tachykinin NK1, NK2 and NK3 receptors. Scyliorhinin I behaved as a full agonist at tachykinin NK1 receptors of the guinea-pig ileum longitudinal muscle and at NK2 receptors of the rabbit pulmonary artery and hamster trachea. In these three preparations scyliorhinin I was as potent agonist as substance P methylester and neurokinin A, respectively. Evidence for activation of tachykinin NK1 and NK2 receptors by scyliorhinin I was obtained by using the selective tachykinin antagonists FK 888, MEN 10,376 and L 659,877. Scyliorhinin I was poorly active as an agonist at NK3 receptors of the rat portal vein. Among scyliorhinin I analogues, [beta-(2-naphthyl)-Ala7]scyliorhinin I, [Val7]scyliorhinin I and [Ile7]scyliorhinin I were 3-25 times weaker than scyliorhinin I itself at NK1 and NK2 receptors. [Phe7]scyliorhinin I, [Phe(F)7]scyliorhinin I and [Phe(Cl)7]scyliorhinin I were as potent as scyliorhinin I at NK1 receptors in the guinea-pig ileum, while they showed 10-30 times lower affinity than scyliorhinin I for NK2 receptors. The present results are discussed in relation to the importance of position 7 in determining the potency and selectivity of scyliorhinin I analogues at tachykinin receptors.
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PMID:Effect of scyliorhinin I and synthetic scyliorhinin I derivatives at mammalian tachykinin NK1, NK2 and NK3 receptors. 750 85

1. The effect of removal of the longitudinal muscle-myenteric plexus (LM-MP) and/or indomethacin (10 microM) on the response to the tachykinin NK-2 receptor selective agonist, [beta Ala8]NKA(4-10), or to the NK-3 receptor selective agonist, senktide, was investigated by measuring mechanical activity (isotonic recording) of circular muscle (ring preparation) of the guinea-pig ileum. 2. Indomethacin (10 microM) increased the percentage of ileal rings displaying spontaneous activity, either intact or LM-MP-free. The response to senktide (10 nM and 1 microM) was lower in LM-MP-free than in intact ileal rings, either in the absence or presence of indomethacin. The response to a low concentration (10 nM) of [beta Ala8] NKA (4-10) was enhanced in LM-MP-free rings and by indomethacin. 3. In intact ileal rings, the response to senktide was unaffected by atropine (3 microM) alone or by the tachykinin NK-2 receptor antagonist MEN 10,376 (10 microM) alone while it was reduced by the combined administration of the two antagonists. The response to senktide was greatly reduced by tetrodotoxin (TTX, 1 microM). Senktide-induced contractions (10 nM) were also reduced by the blocker of N-type voltage-sensitive calcium channels, omega-contoxin (CTX, 0.1 microM). 4. In about 30% of preparations tested, an inhibitory response (decrease in spontaneous activity) to 10 nM senktide, was disclosed in CTX-treated intact ileal rings. This inhibitory effect was TTX-sensitive. 5. In LM-MP-free ileal rings, the response to senktide was abolished or reduced by atropine and MEN 10,376, alone or in combination, and was also reduced or abolished by TTX and CTX. 6. The response to [beta Ala8]NKA (4-10) was inhibited by MEN 10,376, in both intact and LM-MP-free ileal rings while it was unaffected by atropine, TTX or CTX. 7. These results indicate that indomethacin pretreatment induces a regular background activity for studying the motor response to tachykinins in the circular muscle of the ileum, probably by blocking the formation of relaxant prostanoids. A further increase in sensitivity to direct smooth muscle stimulation (NK-2 receptor agonist) can be obtained by removal of the LM-MP. The response to NK-3 receptor stimulation is diminished but not abolished by removal of the LM-MP, suggesting that NK-3 receptors are located on neuronal bodies of myenteric neurons, but possibly also at other sites (possibly, nerve terminals).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effect of longitudinal muscle-myenteric plexus removal and indomethacin on the response to tachykinin NK-2 and NK-3 receptor agonists in the circular muscle of the guinea-pig ileum. 751 89

The potent contractile responses of guinea-pig airways to neurokinin A (NKA) and neuropeptide gamma (NP gamma) are thought to be mediated by NK-2 receptors. However, NK-2 binding sites are not detectable using the radioligand [125I]-iodohistidyl-NKA. Here, a novel, highly selective iodinated radioligand, [125I]-[Lys5,Tyr(I2)7,MeLeu9,Nle10]-NKA(4-10), and a number of related peptides have been used to characterize NK-2 receptors on guinea-pig airways, using binding and functional studies. Specific binding of [125I]-[Lys5,Tyr(I2)7,MeLeu9,Nle10]-NKA(4-10), was saturable and to a single high affinity site, with KD 1.29 +/- 0.36 nM (n = 4). The rank order of potency for tachykinins and analogues as competitors for the binding was: [Lys5,Tyr(I2)7,MeLeu9,Nle10]-NKA(4-10) > or = NP gamma > or = [Lys5,MeLeu9,Nle10]-NKA(4-10) > NKA > or = SR 48968 >> MDL 29913 > or = substance P (SP) = [127I]-Bolton-Hunter NKA (BHNKA) > or = MEN 10207 > neurokinin B (NKB). Septide, [DPro9,Pro10,Trp11]-SP, the NK-1 selective ligands [Sar9,Met(O2)11]-SP, [Pro9]-SP and CP 96345, the NK-3 selective senktide, and calcitonin gene-related peptide (CGRP) were weak or ineffective. On guinea-pig isolated bronchi, the potency order of contractile agonists was: [Lys5,MeLeu9,Nle10]-NKA(4-10) > NKA > or = NP gamma > or = [Lys5,Tyr7,MeLeu9, Nle10]-NKA(4-10) > or = septide = BHNKA > or = [Lys5,Tyr(I2)7,MeLeu9,Nle10]-NKA(4-10) > or = [Sar9,Met(O2)11]-SP > or = NKB = [Pro9]-SP > or = SP >> senktide.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Evidence for tachykinin NK-2 receptors in guinea-pig airways from binding and functional studies, using [125I]-[Lys5,Tyr(I2)7,MeLeu9,Nle10]-NKA(4-10). 751 96


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