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)

1. Intravenous administration of three mammalian tachykinins (substance P, neurokinin A and neurokinin B) and three non-mammalian tachykinins (physalaemin, eledoisin and kassinin) induced dose-dependent increases in vascular permeability, as measured by Evans blue leakage technique, in various segments of the lower urinary tract (bladder dome and neck, proximal urethra, ureters) in urethane-anaesthetized rats. 2. Plasma extravasation induced by substance P (3.71 nmol kg-1 i.v.) was unaffected by pretreatment with antihistaminic drugs or methysergide. 3. A comparison of the relative potencies of various tachykinins did not allow characterization of a distinct type of receptor involved in the increase in vascular permeability. 4. The effects of tachykinin-related peptides which are selective agonists at the NK-1 (substance P-methylester, [Pro9]-SP-sulphone), NK-2 receptor [( Nle10]-NKA(4-10] or NK-3 receptor [( MePhe7]-NKB(4-10) and Senktide) indicated that NK-1 agonists are effective in the whole lower urinary tract, while NK-2 or NK-3 agonists are inactive or weakly active. 5. [beta-Ala4, Sar9]-SP(4-11)-sulphone, a selective NK-1 receptor agonist devoid of histamine-releasing properties, was highly potent and effective in producing plasma extravasation in the rat lower urinary tract. 6. These findings indicate that NK-1 receptors mediate the effect of intravenous tachykinins on vascular permeability in the rat lower urinary tract, through a histamine-independent mechanism.
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PMID:Effects of tachykinins and selective tachykinin receptor agonists on vascular permeability in the rat lower urinary tract: evidence for the involvement of NK-1 receptors. 247 7

Analogues highly selective for receptors for substance P [beta-Ala4,Sar9,Met(02)11]-SP(4-11), for neurokinin A, [Nle10]-NKA(4-10), and for neurokinin B, [beta-Asp4,MePhe7]-NKB(4-10), were administered intraarterially before and after atropine or tetrodotoxin, to characterize the locations on nerve and muscle of the different receptor subtypes in the canine antrum, pylorus and duodenum. Circular muscle strips from each region were also studied in vitro. The NK-2 receptors in the antrum and the pylorus were located postsynaptically on smooth muscle. The NK-3 receptors, on the other hand, were located on neuronal sites in the antrum and duodenum. NK-1 receptors were located on neuronal and nonneuronal sites in the antrum, pylorus and duodenum. Only nonneural receptors could be activated in vitro.
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PMID:The actions of neurokinins and substance P in canine pylorus, antrum and duodenum. 247 89

Sensitive afferent nerves and the neurokinins they release upon activation are considered to be important in controlling bronchomotor tone. Human isolated bronchi respond to neurokinin A (NKA), substance P (SP), and neurokinin B (NKB) with dose-dependent contractions. The order of potency of the three natural neurokinins is NKA greater than SP greater than NKB, suggesting the presence of NK-2 receptors. To further characterize the neurokinin receptors in human bronchi, we used selective agonists for each receptor type (i.e., NK-1, NK-2, and NK-3). In fact, NK-1 selective compounds, [Pro9]SP(1-11) sulfone and [beta-ala4,Sar9]SP(4-11) sulfone, did not induce significant contractions up to 10(-5) M. Similarly, the selective agonist for the NK-3 receptor, [MePhe7]NKB(4-10), was almost inactive. However, the NK-2 selective fragment [Nle]NKA(4-10) was a potent stimulant. The negative log of the peptide concentration that caused 50% of maximal effect (pD2) was 6.99 for NKA and 6.12 for [Nle10]NKA(4-10). Removal of the epithelium significantly enhanced the contractile responses to the three neurokinins and also to the NK-2 selective agonist. Phosphoramidon, an enkephalinase inhibitor, was more potent than epithelium removal in enhancing the contractile responses to these agonists. However, epithelium removal and phosphoramidon did not increase the weak responses to the NK-1 and NK-3 selective compounds. In the presence of phosphoramidon, removal of the epithelium slightly enhanced the contractile responses to NKA and [Nle]NKA(4-10) but not to SP and NKB.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of neurokinin effects and receptor selectivity in human isolated bronchi. 247 56

1. Muscularis mucosae of the distal oesophagus of the opossum contracts in response to substance P and to a variety of tachykinins. To delineate the nature of the receptors present in this tissue, we evaluated contractile responses to substance P, neurokinin A, neurokinin B, eledoisin and analogues believed to be highly selective for NK-1, NK-2 and NK-3 receptors. In addition, the effects of prolonged exposure to each of these agents (10(-6) M or 10(-5) M) on contractile responses to substance P and to itself were evaluated. Similarly effects of prolonged exposure to the various tachykinins and their analogues on the field-stimulated responses of this muscle were studied. 2. All naturally occurring tachykinins were full agonists and differed in potency (comparing ED50 values) by less than ten fold. In nearly all cases there was cross tachyphylaxis between substance P and the other tachykinins and each reduced tonic responses to field stimulation, a response previously shown to be mediated by a substance P like agent. Eledoisin failed to cause tachyphylaxis under the conditions of these experiments. 3. When highly selective tachykinin analogues were used, only that believed to activate NK-1 receptors was a full agonist. [beta-Ala4,Sar9,MetO2(11)]SP(4-11) was also only slightly less potent than substance P. In contrast, an agonist selective for NK-2 (NK-A) receptors, [Nle10]NKA(4-10), and one selective for NK-3 (NK-B) receptors, [beta-Asp4, MePhe7]NKB(4-10) were unable to produce a response equal to 50% of the maximum even at 10(-5) M. However, all three selective tachykinin analogues reduced responses to substance P but not to carbachol. They usually reduced both phasic and tonic responses to field stimulation. 4. We conclude, based on this and earlier study, that the tachykinin receptors of opossum oesophagus muscularis mucosae recognize all naturally occurring tachykinins but may represent only NK-1 receptors. The ability of analogues selective for other types of tachykinin receptors to reduce responses to substance P raises the possibility that their selectivity depends in part on diminished efficacy rather than totally on diminished affinity at some classes of receptor.
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PMID:Classification of tachykinin receptors in muscularis mucosae of opossum oesophagus. 247

This study characterizes the actions of the neurokinins and calcitonin-gene related peptide (CGRP) on electrolyte transport across the mucosa of the guinea pig jejunum in vitro in a modified Ussing chamber. By following changes in short circuit current (Isc) induced by substance P (SP) and neurokinins A & B (NKA & NKB) in the presence and absence of tetrodotoxin (TTX) and atropine, it was established that two distinct neurokinin receptors are involved in the regulation of electrolyte transport. NKA preferentially activates a neuronal receptor since the actions of this neurokinin were inhibited by both TTX and atropine. SP, whose actions were reduced to a lesser extent by TTX and atropine, is considered to activate preferentially a receptor on the epithelial cells. The third neurokinin, NKB, appears to act non-selectively on both the neuronal and epithelial receptors. CGRP, which per se did not affect Isc, markedly potentiated the increases in Isc induced by SP and NKB, and thus acts synergistically with the epithelial neurokinin receptor. These results suggest that two distinct neurokinin receptors (the NK-1 and the NK-2) regulate epithelial transport in the jejunal mucosa of the guinea pig, and furthermore indicate that at least one of the peptides found in enteric nerves (i.e. CGRP) modulates the actions of neurokinins on epithelial cells.
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PMID:Regulation of epithelial transport in the jejunal mucosa of the guinea pig by neurokinins. 247 59

Mammalian tachykinins (substance P, neurokinin A and neurokinin B) produced a concentration-related contraction of the hamster isolated trachea with the following order of potency: NKA congruent to NKB much greater than substance P (SP). NKA and NKB were 280 and 203 times more potent than SP, respectively. The action of NKA, NKB or SP was not significantly modified in presence of thiorphan (10 microM), atropine (1 microM), mepyramine (1 microM) or indomethacin (5 microM). [Nle10]NKA-(4-10) or [beta Ala8]NKA-(4-10), two selective NK-2 receptor agonists, displayed good activity while other synthetic agonists, selective for NK-1 or NK-3 receptors, had little or no effect. The contractile response to tachykinins did not undergo appreciable desensitization and was promptly reversed by washing out. These data indicate that NK-2 receptors are the main if not the sole mediators of the response of the hamster isolated trachea to tachykinins, whose action is independent from cholinergic nerves, histamine release or prostaglandin production. Further, no significant peptide degradation by a thiorphan-sensitive mechanism occurs in this organ.
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PMID:The hamster isolated trachea: a new preparation for studying NK-2 receptors. 247 73

The effects on plasma extravasation of three increasing doses from 6.5 pmol to 650 nmol/kg of substance P (SP), SP fragments, neurokinin A (NKA), neurokinin B (NKB) and selective agonists for neurokinin receptors were assessed in three cutaneous tissues (skin of hind paws, dorsal skin and ears) by intravenous (i.v.) administration in the pentobarbitone anaesthetized rat. Dose-dependent increases in plasma extravasation were observed with the following rank orders of potency (SP greater than NKA greater than NKB) for neurokinins and (SP greater than [p-Glu6]SP(6-11) greater than SP(4-11) greater than [p-Glu5]SP(5-11) greater than SP(7-11] for C-terminal SP fragments. The metabolically stable SP analogue [p-Glu5, MePhe8, Sar9]SP(5-11) was slightly more potent than [p-Glu5]SP(5-11). The N-terminal fragments SP(1-4), SP(1-7) and SP(1-9) were inactive up to 650 nmol/kg. The NK-1 receptor selective agonists [Sar9, Met(O2)11]SP and [beta-Ala4, Sar9, Met (O2)11]SP(4-11) were more potent than the NK-2 [( Nle10]NKA(4-10] and NK-3 [( MePhe7]NKB and [beta-Asp4, MePhe7]NKB(4-10] receptor selective agonists. Plasma extravasation induced by SP (6.5 nmol/kg) was unchanged in the presence of atropine, methysergide, diphenhydramine or during the i.v. and intra-arterial (i.a.) infusion of D-Arg0[Hyp3.D-Phe7]BK, an antagonist of bradykinin. Plasma extravasation induced by SP and [Sar9, Met(O2)11]SP was significantly reduced by indomethacin while that induced by NKA, NKB, [beta-Ala4, Sar9, Met(O2)11]SP(4-11), SP(4-11) and [p-Glu6]SP(6-11) was unaffected by the cyclooxygenase inhibitor. Compound 48/80 (0.75 mg/kg), histamine (10 mg/kg) and 5-HT (10 mg/kg) caused an increase in plasma extravasation, only the effect of compound 48/80 was abolished by indomethacin. Pretreatment with compound 48/80 prevented its own action on plasma extravasation and significantly reduced that induced by 6.5 nmol/kg of SP. These results rule out the involvement of acetylcholine (muscarinic receptors), 5-HT (5-HT1 and 5-HT2 receptors), histamine (H1 receptors) and kinins (B2 receptors) in the response to SP and indicate that the two positively charged amino acids (Arg, Lys) at the N-terminal end of the SP molecule are essential to trigger the release of prostaglandins from mast cells. This mechanism is responsible for the indirect effect of SP and related peptides on capillary permeability and does not appear to be mediated by a selective SP receptor. In addition, neurokinins may increase capillary permeability by direct activation of a NK-1 receptor type on the vascular endothelium.
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PMID:Capillary permeability induced by intravenous neurokinins. Receptor characterization and mechanism of action. 247 92

Polymorphonuclear leukocytes (PMNL) are a component of the inflammatory response to neurogenic mediators. Using the micropore filter approach, the authors studied the chemoattracting properties of tachykinins, including substance P (SP), neurokinin A (NKA) and neurokinin B (NKB), and that of calcitonin gene-related peptide (CGRP) for human PMNL in vitro and now show that SP in near nanomolar concentrations stimulates locomotion of human PMNL. Locomotion of PMNL is induced by SP, aminoterminal SP (1-9) and the SP receptor antagonist [D-pro2, D-trp7,9]-SP (DPDT) but not by carboxyterminal SP (3-11), NKA, NKB, or CGRP suggesting that the aminoterminal amino acids arginine and proline are essential residues of SP in activation of PMNL locomotion. In contrast, the migratory effect of SP on monocytes resides in the carboxyterminal SP amino acid sequence, which is in agreement with carboxyterminal, SP receptor-mediated chemotaxis of human monocytes previously shown by others. From the known structure-activity relationships for SP receptors it is concluded that induction of PMNL migration by SP does not involve neurokinin-1 (NK-1), NK-2 or NK-3 receptors. "Checkerboard" analysis reveals that PMNL locomotion by SP is not dependent on concentration gradients and thus represents chemokinesis, which is enhancement of speed and/or frequency of locomotion. One cannot exclude that this action of SP on PMNL is mediated by the aminoterminal sequence via yet unknown SP "receptors".(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:In vitro human polymorphonuclear leukocyte chemokinesis and human monocyte chemotaxis are different activities of aminoterminal and carboxyterminal substance P. 247 93

1. KCl, carbachol, neurokinin A and endothelin produced concentration-dependent contractions of mucosa-free muscle strips from the dome of the human urinary bladder. The maximal response to carbachol or neurokinin A exceeded that to KCl, while the maximal response to endothelin approached that to KCl. 2. Nifedipine (1 microM) abolished the response to KCl, reduced the response to carbachol or neurokinin A but had no effect on the response to endothelin. Bay K 8644 (1 microM) markedly potentiated the response to KCl but had little or no effect on the response produced by the other stimulants. 3. Superfusion of the strips with a nominally calcium (Ca)-free medium containing EDTA (1 mM) for 30 min markedly reduced the response to carbachol, neurokinin A and endothelin, although a small response was still evident at high concentrations. Likewise, after a prolonged (60 min) superfusion of the strips with a high K (80 mM) Ca-free medium plus EDTA (1 mM) these three agonists still produced a small contractile response. 4. The nifedipine (1 microM) resistant response to carbachol, neurokinin A or endothelin was markedly depressed by LaCl3 (1 mM). In contrast, the nifedipine-(1 microM) resistant response to carbachol was not modified by NiCl2 (0.1 mM) or omega-conotoxin (0.1 microM). 5. Caffeine produced divergent effects depending upon the temperature of incubation: a relaxation at 37 degrees C and a concentration-dependent (2.5-20 mM) contraction at 25 degrees C. The latter was markedly inhibited by procaine (3 mM) but unaffected by nifedipine (1 microM). 6. After a prolonged (60 min) superfusion with a high K, Ca-free medium containing EDTA the response to carbachol (100 microM) was abolished by previous exposure to procaine (3 mM). Conversely, the response to endothelin (1 microM) was unaffected by procaine. The response to endothelin in these experimental conditions was also resistant to LaCl3 (1 mM). 7. These findings indicate that multiple sources of Ca are mobilized for contraction of the human bladder muscle by different stimulants. Dihydropyridine- and voltage-sensitive Ca channels provide the major if not the sole source of Ca for the response to KCl, play some role in the response to muscarinic (carbachol) or NK-2 tachykinin receptor stimulation but are not involved in the response to endothelin. Carbachol, neurokinin A and endothelin all mobilize a Ca pool (either extracellular or located at membrane level) which is LaCl3-sensitive but nifedipine-resistant. Neither T- nor N-type channels appear to be involved in the response to carbachol. In addition, these agents mobilize a tightly bound Ca pool independently from membrane depolarization. This latter pool is probably a procaine-sensitive intracellular source of activator Ca mobilized by caffeine and carbachol. The failure of procaine to prevent the response to endothelin in high K, Ca-free medium raises the possibility that this peptide mobilizes an intracellular source of activator Ca, distinct from the caffeine- and carbachol-sensitive pool.
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PMID:Multiple sources of calcium for contraction of the human urinary bladder muscle. 248 Jan 67

1. Muscle strips from the dome of the human urinary bladder responded to field stimulation with contractions which were atropine- (3 microM) and tetrodotoxin- (1 microM) sensitive. These contractions were sensitive to omega conotoxin (CTX, 0.1 microM). The atropine- and tetrodotoxin-resistant contractions produced by field stimulation were totally unaffected by CTX. 2. DMPP (30-100 microM), a nicotinic agonist, produced transient bladder contractions which were hexamethonium- and atropine-sensitive. 3. Tachykinins produced a contraction of the human bladder. Among several synthetic tachykinin analogs only those having activity at the NK-2 receptor produced a consistent contractile response. 4. Either capsaicin (1 microM) or calcitonin gene-related peptide (10 nM-0.1 microM) had no motor effect. At 10 microM, capsaicin exerted a depressant effect on nerve-mediated contractions but this effect did not exhibit desensitization. 5. These findings provide evidence that NK-2 receptors are the main if not the sole mediators of the contractile response of the muscle from the dome of the human isolated bladder to tachykinins. 6. No evidence was found for a tachykininergic component in the excitatory response to field stimulation nor for motor responses mediated by capsaicin-sensitive nerves. 7. CTX-sensitive calcium channels are probably present on cholinergic nerve terminals in the human bladder muscle.
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PMID:Further studies on the motor response of the human isolated urinary bladder to tachykinins, capsaicin and electrical field stimulation. 248 3


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