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

The metabolism of several tachykinin antagonists by membrane peptidases has been examined. [beta Ala8]NKA(4-10) was not stabilized against degradation by endopeptidase-24.11 and this was the major activity in renal brush border membranes hydrolyzing this peptide. The antagonist MEN 10263 was much more resistant to hydrolysis by endopeptidase-24.11, although hydrolysis of the C-terminal Leu-Phe bond was detectable. Three other tachykinin receptor antagonists (MEN 10208, MEN 10207, and MEN 10376), by virtue of D-Trp substitutions, were rendered resistant to endopeptidase-24.11 but were still susceptible to aminopeptidase action. These studies provide further insight into design features necessary to produce metabolically stable peptide analogues.
 ...
PMID:Metabolic stability of some tachykinin analogues to cell-surface peptidases: roles for endopeptidase-24.11 and aminopeptidase N. 765 97

The ascending reflex contraction of intestinal circular muscle involves both cholinergic and tachykininergic transmission, which are thought to be activated by different degrees of distension. Substance P, however, is colocalized with acetylcholine in myenteric neurons, and the present study examined the role of these transmitter substances in relation to low- and high-degree distension and with regard to ascending propagation of excitation. Reflex contractions in segments of the guinea pig isolated small intestine were evoked by inflation of an intraluminal balloon and recorded orally to the site of distension. Atropine (12.5 nM), hexamethonium (3 microM) and the neurokinin (NK)2-selective tachykinin antagonist MEN 10,376 (10 microM) inhibited contractions induced by low-degree distension to a larger extent than contractions induced by high-degree distension, whereas the receptor-nonselective tachykinin antagonist spantide (30 microM) did not differentiate in this way. Atropine, hexamethonium and spantide also depressed the propagation of excitation, i.e., the response recorded 2 cm away from the distension site was inhibited to a larger degree than the response recorded 1 cm away from the distension site. In contrast, MEN 10,376 did not interfere with the ascending propagation of excitation, and the NK1-selective tachykinin antagonist GR 82,334 (10 microM) was without effect on the ascending reflex contraction. These observations show that tachykinins and acetylcholine comediate ascending reflex contractions triggered by both low- and high-degree distension. When seen in context with the known projection of myenteric neurons, the findings relating to the ascending propagation of excitation indicate that NK2 receptors participate in neuromuscular transmission only, whereas neuroneuronal transmission involves both nicotinic and muscarinic acetylcholine receptors.
 ...
PMID:Ascending enteric reflex contraction: roles of acetylcholine and tachykinins in relation to distension and propagation of excitation. 767 49

We have investigated the ability of compound 48/80 and of histamine H1 and H2 receptor antagonists to inhibit toluene diisocyanate-induced contractions in isolated guinea-pig bronchi. Compound 48/80 (100 micrograms/ml) significantly inhibited toluene diisocyanate-induced contractions. By contrast, the two histamine H1 and H2 receptor antagonists, chlorpheniramine (10 microM) and cimetidine, (10 microM) did not affect toluene diisocyanate-induced contractions, but significantly inhibited contractions induced by exogenously applied histamine (100 microM) and by 48/80. We investigated which mechanisms 48/80 used to inhibit toluene diisocyanate-induced contractions, paying particular attention to the possible involvement of capsaicin-sensitive primary afferents. In vitro capsaicin desensitization (10 microM for 30 min followed by washing) significantly reduced compound 48/80-induced contractions. A capsaicin-resistant component of contraction was also evident. Ruthenium red (3 microM), an inorganic dye which acts as a selective functional antagonist of capsaicin, did not affect 48/80-induced contraction. MEN 10,207 (Tyr5,D-Trp6,8,9,Arg10)-neurokinin A (4-10) (3 microM) a selective antagonist of NK2-tachykinin receptors significantly reduced 48/80-induced contractions. These results show that compound 48/80 inhibits toluene diisocyanate-induced contractions in isolated guinea-pig bronchi. It is likely that two mechanisms are involved in the inhibition: (1) the release of mediators other than histamine by mast cells, (2) an effect of 48/80 on sensory nerves.
 ...
PMID:The effect of compound 48/80 on contractions induced by toluene diisocyanate in isolated guinea-pig bronchus. 768 59

1. Neuromuscular transmission in the circular muscle of the canine proximal colon was examined, in the presence and absence of nitric oxide synthase inhibitors, by use of mechanical and intracellular microelectrode recording techniques. 2. Electrical field stimulation (EFS; 0.1-20 HZ) produced frequency-dependent contractions of circular muscle strips which reached a maximum at 15 Hz. These responses were enhanced by NG-monomethyl-L-arginine (L-NMMA; 300 microM) and reduced by atropine (1 microM). The effects of L-NMMA were reversed by L-arginine (3 mM). All responses to EFS were abolished by tetrodotoxin (1 microM). 3. In the presence of atropine, phentolamine and propranolol (all at 1 microM; 'non-adrenergic, non-cholingergic (NANC) conditions'), EFS evoked frequency-dependent inhibition of phasic contractions which reached a maximum at 5 Hz. At higher frequencies of EFS, inhibition diminished, and these responses were followed by post-stimulus excitation. 4. Under NANC conditions and in the presence of L-NG-nitroarginine methyl ester (L-NAME; 200 microM), EFS evoked contractions at frequencies of 5 Hz or greater. These contractions were reduced by co-incubation with L-arginine (2 mM) and abolished by tetrodotoxin (1 microM). 5. In the presence of atropine (1 microM), EFS (5-20 Hz) caused frequency-dependent inhibition of electrical slow waves. In the presence of L-NAME (100 microM) and atropine, the inhibitory response to EFS was abolished and an increase in slow wave duration was seen at stimulation frequencies greater than 5 Hz. The effects of EFS on slow wave duration were abolished by tetrodotoxin (1 microM). 6. Atropine-resistant contractions to EFS were enhanced by indomethacin (10 microM) and reduced or abolished by the non-selective NK1/NK2 tachykinin receptor antagonist D-Pro2, D-Trp7,9 SP, and by the selective NK2 receptor antagonist MEN 10,376 (10 microM).7. Exogenous tachykinins mimicked non-cholinergic excitatory electrical and mechanical responses. The rank order of potency for contraction was neurokinin A>neurokinin B>substance P, suggesting a predominance of the NK2 sub-type of tachykinin receptors on colonic smooth muscle cells. Low concentrations of neurokinin A also increased the amplitude and duration of electrical slow waves.8. These results suggest that: (i) in previous studies, non-cholinergic excitatory responses were masked by the simultaneous release of NO; (ii) non-cholinergic excitatory responses occur throughout the period of stimulation and are not manifest only as 'rebound' excitation; (iii) one or more tachykinins, possibly,acting via NK2 receptors, may mediate non-cholinergic excitatory responses.
 ...
PMID:Inhibition of nitric oxide synthesis reveals non-cholinergic excitatory neurotransmission in the canine proximal colon. 768 1

Neurokinin binding sites are distributed throughout the central and peripheral nervous system and three neurokinin binding sites have been described until now. The endogenous tachykinins substance P, neurokinin A and eledoisin as well as the highly selective neurokinin ligands [Arg6, Sar9, Met(O2)11]SP6-11 and [Sar9, Met(O2)11]SP (for neurokinin-1), MEN 10,376 and [beta Ala8]NKA(4-10) (for neurokinin-2) and senktide and [MePhe7]NKB (for neurokinin-3) were used for displacement experiments. Neurokinin-1 and -3 binding sites were demonstrated in membrane preparations of rat striatum, frontal cortex, hypothalamus, hippocampus and amygdala by displacing [125I]-BH-substance P and [125I]-BH-eledoisin, respectively. The highly selective neurokinin-2 ligand MEN 10,376 was iodinated to measure neurokinin-2 binding sites, but no specific binding was found in membranes of all brain regions, the spinal cord, the stomach, the urinary bladder or the guinea-pig lung, probably due to loss of binding properties. We conclude that neurokinin-1 and neurokinin-3 binding sites are distributed in several brain regions of the rat brain and selective neurokinin ligands are important tools to characterize neurokinin binding sites.
 ...
PMID:Characterization of neurokinin binding sites in rat brain membranes using highly selective ligands. 769 43

Tachykinins, in particular neurokinin A and substance P, produce a number of airway effects which may contribute to respiratory diseases such as asthma. We examined the ability of aerosolized substance P, neurokinin A or capsaicin to produce respiratory alterations in conscious guinea pigs using modified whole body plethysmography. Substance P-mediated dyspnea and significant respiratory events were inhibited by the NK1 receptor antagonist, CP-96,345. Neurokinin A-mediated respiratory effects were ablated by the NK2 receptor antagonists: MEN 10207, MDL 29,913 and SR 48,968, the latter being the most potent. The peptide-based antagonist, MEN 10207, produced respiratory effects itself suggesting partial agonist activity. The cyclic hexapeptide, MDL 29,913, relaxed airway smooth muscle via mechanisms other than tachykinin antagonism. NK2 but not NK1 receptor antagonists were able to delay the onset of capsaicin-induced dyspnea, although alone they did not usually (in approximately 10% of the animals) eliminate the response. However, when NK2 receptor antagonists were combined with CP-96,345, the incidence of dyspnea induced by capsaicin decreased significantly (40%) suggesting that both tachykinins contribute to dyspnea in this system.
 ...
PMID:Tachykinin-mediated respiratory effects in conscious guinea pigs: modulation by NK1 and NK2 receptor antagonists. 769 93

The mechanism of action of the tachykinin NK2 receptor antagonists, SR 48968 ((S)-N-methyl-N[4-acetylamino-4-phenyl-piperidino)-2-(3,4- dichlorophenyl)butyl]benzamide) and MEN 10,627 (cyclo[(Met-Asp-Trp-Phe-Dap-Leu) cyclo (2 beta-5 beta)]), was compared in the guinea-pig isolated gallbladder and circular muscle of proximal colon by using neurokinin A and [beta Ala8]neurokinin A-(4-10) as agonists. The experiments performed with colon were in the presence of the tachykinin NK1 receptor-selective antagonist, (+/-)-CP-96,345 ([2-(diphenylmethyl)-N-[(2-methoxyphenyl)-methyl]-1- azabicyclo[2,2,2]octan-3-amine]). SR 48968 caused an insurmountable antagonism of tachykinin NK2 receptor-mediated contraction in both preparations; its blockade was essentially irreversible, since it was not reversed by washout (up to 2 h) and was increased by prolonging the incubation from 15 to 120 min. In contrast, MEN 10,627 produced simple competitive antagonism, which was time-independent and fully reversible in both preparations. In both preparations, the simultaneous administration of SR 48968 and MEN 10,627 produced an intermediate antagonism of the responses to the agonists, as compared to the antagonism produced by each antagonist alone. The present results are discussed in the light of the reported interaction of SR 48968 with tachykinin NK2 receptors at a recognition epitope distinct from that of agonist(s).
 ...
PMID:Different mechanism of tachykinin NK2 receptor blockade by SR 48968 and MEN 10,627 in the guinea-pig isolated gallbladder and colon. 769 94

The effect of activation of tachykinin NK2-receptors on gastrointestinal propulsion was studied in vivo in conscious rats. The selective NK2-receptor agonist [beta Ala8]NKA-(4-10) produced an atropine-resistant specific increase of the small intestinal transit measured by the charcoal method. This effect was restricted to the small intestine since gastric emptying was not affected by [beta Ala8]NKA-(4-10). The newly developed polycyclic peptide NK2-receptor antagonist MEN 10,627 produced a dose-dependent inhibition of this stimulated transit. The spasmolytic effect of MEN 10,627 was highly selective because it did not affect stimulated intestinal transit induced by equieffective doses of carbachol and reserpine. These findings indicate that MEN 10,627 is a valuable tool for assessing the role of NK2-receptors in intestinal propulsive activity.
 ...
PMID:Spasmolytic effect of the NK2-receptor-selective antagonist MEN 10,627 in rat small intestine. 779 29

The cyclic pseudopeptides MEN 10,548, MEN 10,581, MEN 10,619, MEN 10,677, MEN 10,777 and MEN 10,867 were studied at tachykinin neurokinin (NK)1, NK2 and NK3 receptors on several in vitro bioassays. All compounds were potent and competitive antagonists at tachykinin NK1 and NK2 receptors of the guinea-pig ileum, rabbit pulmonary artery and hamster trachea, showing the highest affinity for the hamster NK2 receptor (e.g., MEN 10,677: pKB = 9.3). By contrast, none showed affinity for NK3 receptors of the rat portal vein, up to 3 microM. In the guinea-pig isolated bronchus, the pseudopeptide compounds competitively antagonized the NK2 receptor-selective agonist [beta Ala8]-NKA (4-10) with potencies comparable to those shown at the rabbit NK2 receptor. In addition, the pseudopeptides were from 3.5-fold (MEN 10,677) to 16-fold (MEN 10548) more potent antagonists against septide than against [Sar9]SP sulfone, two agonists reportedly selective for two distinct sites/subtypes of the NK1 receptor. In binding experiments at human IM9 cells, the pseudopeptide compounds displaced [3H]substance P from human NK1 receptor, showing similar affinities to those displayed at the NK1 receptor in the guinea-pig ileum or bronchus against substance P methylester or septide, as agonists, respectively. This new class of pseudopeptide antagonists, by showing a comparable and high affinity at both tachykinin NK1 and NK2 receptors, might be proposed for treatment/prevention of airway diseases in which endogenous tachykinins play a role by activation of both receptors.
 ...
PMID:Activity of cyclic pseudopeptide antagonists at peripheral tachykinin receptors. 789 19

1. In the presence of atropine (1 microM) and guanethidine (3 microM), electrical field stimulation (EFS) of the rat isolated urinary bladder for 30 s induced a frequency-dependent (1-30 Hz) nonadrenergic non-cholinergic (NANC) triphasic contraction characterized by a peak response (within 10 s from onset of stimulation), a late response (determined as the tension developed at the end of the stimulation period) and a prolonged post-stimulus 'off' response. The latter peaked at 2-6 min from the end of the stimulation period. At 10 Hz, the amplitude of the three responses averaged 89 +/- 6, 76 +/- 6 and 18 +/- 3% of the response to 40 mM KCl, respectively. Tetrodotoxin (1 microM) abolished all contractile responses to EFS. 2. In capsaicin-pretreated bladder strips (10 microM for 15 min) the amplitude of the peak response to EFS (1-30 Hz for 30 s) was unchanged, the 'late' response to EFS was significantly reduced as compared to controls, and the post-stimulus response was absent, being replaced by a transient relaxation. 3. When varying train duration from 1 to 120 s at a frequency of 10 Hz, the differences between control and capsaicin-treated strips became evident for periods of stimulation > 10 s. 4. The tachykinin NK1 receptor antagonist, SR 140,333 (0.1-1 microM) had no effect on the peak response to EFS (10 Hz for 30 s) while it decreased significantly the late response at both concentrations tested (16 +/- 3 and 33 +/- 3% inhibition). At 1 micro M, SR 140,333 also significantly reduced (29 +/- 9% inhibition)the peak of the post-stimulus contraction. The tachykinin NK2 receptor antagonist, MEN 10,627(0. 1-1 9 MicroM) had no significant effect on the peak response to EFS (10 Hz for 30 s), and decreased the late response at 1 MicroM only (32 +/- 4% inhibition). MEN 10,627 inhibited the post-stimulus response at both concentrations tested and almost abolished it at 1 MicroM.5. The combined administration of SR 140,333 and MEN 10,627 (1 MicroM each) produced a small reduction(22 +/- 3% inhibition) of the peak response to EFS, a marked reduction (48 +/- 3% inhibition) of the late response and the abolition of the post-stimulus response which was replaced by a post-stimulus relaxation as observed in capsaicin-pretreated strips.6. SR 140,333 (0.1 and 1.0 MicroM) produced a large rightward shift in the concentration-response curve tothe NKI receptor agonist, [Sar9]substance P sulphone (apparent pKB 8.97 +/- 0.14), without affecting the response to the NK2 receptor-selective agonist, [Beta Ala8]neurokinin A (4-10). MEN 10,627 (0.1 and 1 MicroM)produced a large rightward shift of the concentration-response curve to [Beta Ala8]neurokinin A (4-10)(apparent pKB 8.95 +/- 0.16) without affecting the response to [Sarl substance P sulphone. SR 140,333 and MEN 10,627 (1.0 MicroM each) did not affect the contraction produced by exogenous ATP (1 mM).7. These findings provide evidence that the NANC contraction of the rat isolated urinary bladder to transmural nerve stimulation has two components, which are sharply differentiated by blockade of the efferent function of sensory nerves following in vitro capsaicin administration. The first component,probably mediated by endogenous ATP, is fully activated during short periods of nerve activity (< 10 s)and does not involve capsaicin-sensitive nerve afferents. The second component, which is capsaicin sensitive and tachykinin-mediated, is evident as a late 'on' response during nerve stimulation and as a post-stimulus 'off response for periods of stimulation >lOs. Activation of both NK1 and NK2receptors contributes to the capsaicin-sensitive responses.
 ...
PMID:Evidence for a capsaicin-sensitive, tachykinin-mediated, component in the NANC contraction of the rat urinary bladder to nerve stimulation. 795 73


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>