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)

We have investigated the effects of CP-99,994 [(+)-(2s,3s)-3-(2-methoxybenzylamino)-2-phenylpiperidine], a tachykinin NK1 receptor antagonist, HOE 140 (D-Arg[Hyp3,Thi5,D-Tic7,Oic8]bradykinin), a bradykinin B2 receptor antagonist, and ketotifen (4-(1-methyl-4-piperidylidene)4 H-benzo[4,5]cycloheptal[1,2-b]thiophen-10(9H)-one hydrogen fumarate), a histamine H1 receptor antagonist with mast cell-stabilizing properties, on microvascular leakage induced by gaseous formaldehyde. Extravasation of Evans blue dye into airway tissues was used as an index of airway microvascular leakage. Leakage of dye in the trachea and main bronchi increased significantly in a concentration-dependent fashion after 10 min inhalation of formaldehyde (5-45 parts per million (ppm)). The airway response induced by 10 min inhalation of 15 ppm formaldehyde (trachea: 119.5 +/- 13.9 ng/mg, n = 7; main bronchi: 139.6 +/- 7.9 ng/mg, n = 7) was abolished by the administration of CP-99,994 (3 and 6 mg/kg i.v.), but not by the administration of HOE 140 (0.65 mg/kg i.v.) nor ketotifen (1 mg/kg i.v.). The increase in vascular permeability induced by formaldehyde in the rat airway was mediated predominantly by NK1 receptor stimulation. Activation of bradykinin receptors and mast cells did not appear to play an important role in this airway response.
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PMID:Role of tachykinin and bradykinin receptors and mast cells in gaseous formaldehyde-induced airway microvascular leakage in rats. 883 17

Doubly protonated substance P and two analogs alkylated at the ninth position was studied to determine the effect of N-alkylation of the amide nitrogen on the electrospray ionization/surface-induced dissociation (ESI/SID) fragmentation pattern. Thermal decomposition experiments and ab initio calculations were also used in conjunction with the ESI/SID experiments. The increase in relative abundances of the product ions resulting from the cleavage of the amide bond at the alkylation site (relative to the corresponding cleavage for substance P) can be explained by the increased basicity of the amide nitrogen in the context of the 'mobile proton' model. The relative abundances of singly charged b ions suggest a rearrangement of the amide hydrogen located N-terminal to the bond cleaved.
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PMID:Effect of alkyl substitution at the amide nitrogen on amide bond cleavage: electrospray ionization/surface-induced dissociation fragmentation of substance P and two alkylated analogs. 891 23

1. Primary afferent neurones releasing the vasodilator, calcitonin gene-related peptide, mediate the gastric hyperaemic response to acid back-diffusion. The tachykinins neurokinin A (NKA) and substance P (SP) are located in the same neurones and are co-released with calcitonin gene-related peptide. In this study we investigated the effect and possible role of tachykinins in the acid-evoked gastric vasodilatation in urethane-anaesthetized rats. 2. Gastric acid back-diffusion, induced by perfusing the stomach with 15% ethanol in the presence of 0.05 M HCl, increased gastric mucosal blood flow by 60-90%, as determined by the hydrogen clearance technique. NKA and SP (0.14-3.78 nmol min-1 kg-1, infused intra-aortically) inhibited the gastric mucosal hyperaemic response to acid back-diffusion in a dose-dependent manner, an effect that was accompanied by aggravation of ethanol/acid-induced macroscopic haemorrhagic lesions. 3. The inhibitory effect of NKA (1.26 nmol min-1 kg-1) on the acid-induced gastric mucosal vasodilatation was prevented by the tachykinin NK2 receptor antagonists, MEN 10,627 (200 nmol kg-1) but left unaltered by the NK1 receptor antagonist, SR 140,333 (300 nmol kg-1) and the mast-cell stabilizer, ketotifen (4.6 mumol kg-1). 4. Under basal conditions, with 0.05 M HCl being perfused through the stomach, NKA (1.26 nmol min-1 kg-1) reduced gastric mucosal blood flow by about 25%, an effect that was abolished by SR 140,333 but not MEN 10,627 or ketotifen. 5. SR 140,333, MEN 10,627 or ketotifen had no significant effect on basal gastric mucosal blood flow nor did they modify the gastric mucosal hyperaemic reaction to acid back-diffusion. 6. The effect of NKA (1.26 nmol min-1 kg-1) in causing vasoconstriction and inhibiting the vasodilator response to acid back-diffusion was also seen when blood flow in the left gastric artery was measured with the ultrasonic transit time shift technique. 7. Arginine vasopressin (AVP, 0.1 nmol min-1 kg-1) induced gastric mucosal vasoconstriction under basal conditions but was unable to inhibit the dilator response to acid back-diffusion. 8. These data show that NKA has two fundamentally different effects on the gastric circulation. Firstly, NKA reduces gastric blood flow by activation of NK1 receptors. Secondly, NKA inhibits the gastric hyperaemic response to acid back-diffusion through an NK2 receptor-mediated mechanism. These two tachykinin effects appear to take place independently of each other since they are mediated by different receptors. This concept is further supported by the inability of AVP to mimic tachykinin inhibition of the gastric vasodilator response to acid back-diffusion.
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PMID:Tachykinin inhibition of acid-induced gastric hyperaemia in the rat. 898 97

The distribution of nitrergic neurons in the pancreas of the newborn guinea pig was first investigated, using nitric oxide synthase (NOS) immunofluorescence and nicotinamide adenine dinucleotide hydrogen phosphate-diaphorase (NADPH-d) histochemistry. There was total colocalization of NOS and NADPH-d in the pancreatic ganglion cells. NADPH-d was then used as a marker for NOS. In the whole mount preparation of the pancreas, most of the nitrergic neurons were located in the head and the body region, along the branches of pancreatic blood vessels. Some were also associated with the main pancreatic duct, islets of Langerhans and pancreatic acini. To investigate whether NADPH-d stained cells were neurons and whether NADPH-d was colocalized with various neuropeptides and dopamine-beta-hydroxylase (D beta H), an enzyme involved in the synthesis of noradrenaline, antibodies against neuron specific enolase (NSE), vasoactive intestinal peptide (VIP), neuropeptide Y (NPY). D beta H, substance P (SP), calcitonin gene-related peptide (CGRP) and bombesin (BOM) were used. Of all NSE positive ganglion cells, 76.8% were NADPH-d positive. NOS, VIP, NPY and D beta H immunoreactivities were found in both the neuronal cell bodies and nerve fibres in the pancreas while SP, CGRP and BOM immunoreactivities were detected only in the nerve fibres. SP-, CGRP- and BOM-containing nerves were in close contact with both NADPH-d positive as well as NADPH-d negative neurons. The percentages of NADPH-d/VIP, NADPH-d/NPY, NADPH-d/D beta H neurons in the total number of pancreatic neurons were 67.4%, 53.5%, 21.5% respectively. With double labelling in adjacent sections three subpopulations of pancreatic ganglion cells were demonstrated: NADPH-d/VIP/NPY, NADPH-d/VIP/D beta H and NADPH-d/NPY/D beta H.
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PMID:Nitrergic neurons in the pancreas of newborn guinea pig: their distribution and colocalization with various neuropeptides and dopamine-beta-hydroxylase. 898 82

Neuropeptide Y (NPY) receptors belong to the G-protein-coupled receptor (GPCR) superfamily and mediate several physiological responses, such as blood pressure, food intake, sedation and memory retention. To understand the interactions between the NPY Y1 receptor subtype and its ligands, computer modeling was applied to the natural peptide agonist, NPY and a small molecule antagonist, BIBP3226. An agonist and antagonist binding domain was elucidated using mutagenesis data for the Y1 receptor as well as for other GPCR families. The agonist and antagonist ligands which were investigated appear to share common residues for their interaction within the transmembrane regions of the Y1 receptor structure, including Gln120, Asn283 and His306. This is in contrast to findings with tachykinin receptors where the binding domains of the non-peptide antagonists have very little in common with the binding domains of the agonist, substance-P. In addition, a hydrogen bond between the hydroxyl group of Tyr36 of NPY and the side chain of Gln219, an interaction that is absent in the model complex between Y1 and the antagonist BIBP3226, is proposed as one of the potential interactions necessary for receptor activation.
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PMID:Modeling the G-protein-coupled neuropeptide Y Y1 receptor agonist and antagonist binding sites. 908 10

Crystal structures of nine non-peptide tachykinin NK1 antagonists have been analysed for the intermolecular interactions of their pharmacophoric groups with neighbouring molecules in the crystals. Experimental data on interaction geometries of these antagonists with their environment can be of help in understanding the mechanism of binding to the human NK1 receptor. Several interaction geometries have been identified that are consistent with both structure-activity relationships and reported receptor interactions for the compounds analysed. In addition, an interaction site for the side-chain of Gln-165 in the human NK1 receptor that is probably involved in donating a hydrogen bond to the benzylamino nitrogen or benzylether oxygen of the quinuclidine and piperidine antagonists is explicitly postulated. Also, a superposition based on pharmacophoric elements in the crystal structure conformations of two prototypic NK1 antagonists, CP-96,345 (1) and CP-99,994 (4), suggests how both compounds might interact with the human NK1 receptor in a similar manner.
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PMID:Possible ligand-receptor interactions for NK1 antagonists as observed in their crystal structures. 911 32

Small peptides ions consisting of a comparable number of amino acid residues but varying in composition and sequence were allowed to undergo gas-phase deprotonation reactions. These multiply protonated ions were generated by electrospray ionization and analyzed in a Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometer. The peptides studied contain 11-14 amino acid residues and included adrenocorticotropic hormone (ACTH) fragment (11-24), fibrinopeptide B (human), gastrin I fragment (1-13) (human), renin substrate tetra-decapeptide (horse), somatostatin, substance P and tyrosine protein kinase. Rate constants were determined for the deprotonation reactions of the peptide ions with a series of reference compounds of known gas-phase basicities ranging from 190.0 to 232.6 kcal mol-1. From these values, apparent gas-phase acidities (GAapp) were assigned to [M + nH]n+ (n > or = 2), of each peptide. All of the multiply charged peptide ions were sequentially deprotonated to the +1 charge state by ion-molecule reactions. The GAapps ranged from 193.3 kcal mol-1 (for [M + 4H]4+ of renin substrate, the ion most readily deprotonated) to > 232.6 kcal mol-1 (for [M + 2H]2+ of ACTH (11-24), the ion most difficult to deprotonate). The proximity of intrinsically basic sites (and therefore potential protonation sites) has an effect on the observed deprotonation rates. Ions experiencing Coulomb repulsion resulting from adjacent protonation sites often show more facile deprotonation. However, the intrinsic basicity of a protonation site also plays a role in determining the case of deprotonation. As a result, some lower charge state peptide ions deprotonate more readily than other peptides with higher charges but with more basic protonation sites. In addition, conformation and the influence of intramolecular hydrogen bonding may affect the reactivity of some peptide ions. Also observed was non-linear kinetic behavior that indicates multiple isomers at certain charge states for some peptides, e.g. [M + nH]n+, (n = 2 and 3) for ACTH 11-24 and [M + 3H]3+ for somatostatin.
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PMID:Reactivity and gas-phase acidity determinations of small peptide ions consisting of 11 to 14 amino acid residues. 931 Nov 49

1. Peroxynitrite (ONOO-) is a cytotoxic species, formed by the reaction between nitric oxide and superoxide free radicals, that may be involved in inflammation. In this study we have investigated the effect of peroxynitrite on plasma extravasation and microvascular blood flow in the dorsal skin and on nociceptive responses in the hind paw of the rat. 2. Male Wistar rats were anaesthetized and their dorsal skin shaved. Plasma extravasation was measured by the extravascular accumulation of 125I-labelled albumin over 0-45 min and 0-240 min. Blood flow was measured by laser-Doppler flowmetry over 0-240 min. Studies in the hind paw were carried out in the conscious rat. Hind paw weight changes were determined by volume displacement and nociception by a mechanical hyperalgesia technique. 3. Intradermal (i.d.) peroxynitrite (100-200 nmol site-1) produced a significant (P < 0.01) dose-dependent increase in plasma extravasation in dorsal skin over 0-45 min which was not increased over 45-240 min. Plasma extravasation was significantly (P < 0.001) decreased in rats pretreated with the anti-inflammatory steroid dexamethasone (1 mg kg-1, i.v.; -180 min), but not modulated by treatment with the hydrogen peroxide deactivator catalase (2200 u site-1), or the superoxide scavenger superoxide dismutase (500 u site-1), effective doses of the tachykinin NK1 antagonist SR140333 (1 nmol site-1), the cyclo-oxygenase inhibitor indomethacin (358 mumol site-1), or combined pretreatment with mepyramine (histamine H1-receptor antagonist; 2.8 nmol site-1) and methysergide (5-HT antagonist; 1.9 nmol site-1). 4. Microvascular blood flow was significantly (P < 0.05) increased 30 and 120 min after i.d. peroxynitrite (100 nmol site-1) in dorsal skin and remained raised until the end of the recording period (240 min). The increase in blood flow was unaffected by dexamethasone (1 mg kg-1, i.v.; -180 min) or indomethacin (10 mg kg-1, s.c.; -30 min). 5. Hind paw volume was significantly (P < 0.001) increased 30 min after intraplantar peroxynitrite (87.5 and 175 nmol paw-1) and remained raised for the duration of the experiment (360 min). By comparison, nociception was not altered by intraplantar peroxynitrite. 6. These data indicate that peroxynitrite can cause an increase in both plasma extravasation and blood flow, suggesting that peroxynitrite could be of biological relevance to microvascular responses. These findings may be of importance in the pathology of inflammatory diseases in which peroxynitrite formation occurs.
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PMID:Effect of peroxynitrite on plasma extravasation, microvascular blood flow and nociception in the rat. 940 73

Since exogenously applied tachykinins (substance P and neurokinin A) prevent the neurogenic hyperaemia which is elicited by acid back-diffusion in the rat stomach, we investigated whether endogenous tachykinins would act in a similar manner. Acid back-diffusion, induced by perfusing the stomach with 15% ethanol in the presence of 0.05 M HCI, increased gastric mucosal blood flow (GMBF) by 60-100% as determined by hydrogen clearance in urethane-anaesthetized rats. This response remained unchanged after pretreatment with the tachykinin NK1 receptor antagonist SR 140,333 (300 nmol/kg) but tended to be enhanced by the NK2 receptor antagonist MEN 10,627 (200 nmol/kg). When given during ongoing acid back-diffusion, MEN 10,627 significantly enhanced the acid-evoked vasodilatation as compared with vehicle or SR 140,333. We conclude that endogenously released tachykinins, acting via NK2 receptors, limit the gastric hyperaemic response to acid.
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PMID:Inhibition of acid-induced hyperaemia in the rat stomach by endogenous NK2 receptor ligands. 945 33

Nitrergic and peptidergic innervation of the chick thymus was studied using histochemical and immunohistochemical methods. Nicotinamide adenine dinucleotide hydrogen phosphate-diaphorase (NADPH-d) histochemistry and anti-nitric oxide synthase (NOS) antibodies stained both nerve fibres and 'neuron-like' cells located in the septal connective tissue. NADPH-d and NOS were partially colocalised. Staining of NADPH-d positive neuron-like cells with the neuronal marker, neuron specific enolase, confirmed the neuronal nature of these cells. Antibodies against vasoactive intestinal peptide (VIP), neuropeptide tyrosine (NPY), substance P (SP) and calcitonin gene related peptide (CGRP) were used to map the peptidergic innervation of the chick thymus. The distribution of nerve fibres staining for the various neuroactive chemicals in specific thymic compartments was non-uniform. Out of all the peptides, VIP-containing nerves appeared to be the most abundant. In addition, double-labeling of the thymic sections revealed that VIP and NADPH-d were colocalised in the neuronal structures. Immunostaining of the chick embryos demonstrated that VIP, NPY, SP and CGRP were first expressed in the chick thymus during late ontogeny. The significance of these novel findings was discussed.
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PMID:Nitrergic, peptidergic and substance P innervation of the chick thymus. 947 19


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