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)

Dynorphin A(1-17), the proposed endogenous ligand for the kappa receptor, has been reported to demonstrate no antinociceptive activity when tested in analgesic assays involving noxious (heat (e.g., tail-flick and hot-plate assays). By using a rat tail-flick analgesic assay that utilizes extreme cold as its noxious stimulus (an ethylene glycol-water mixture maintained at -10 degrees C), we have recently reported a dose-related and naloxone-reversible antinociceptive effect for i.c.v. administered dynorphin A(1-17). To elucidate the biochemical mechanism of this antinociception, we designed a push-pull perfusion system which would allow us to measure changes in neuropeptide release in the spinal cord during exposure to noxious heat or cold. Male Sprague-Dawley rats were implanted surgically with two lengths of PE-10 tubing inserted into the spinal subarachnoid space via the cisterna magna, with the push cannula at the level of T-1, and the pull cannula at the rostral edge of the lumbar enlargement. At the time of testing, samples of cerebrospinal fluid were collected both in the presence and absence of a noxious stimulus. Substance P (SP) and somatostatin (SST) levels were measured by radioimmunoassay. Exposing the animal's tail to the noxious cold (30 sec/min for 20 min) resulted in a significant elevation in SP release (69% above base-line levels), but no change in the level of SST release. Conversely, exposure to noxious heat (50 degrees C, 20 sec/min for 20 min) produced a significant increase in SST release (56% above base line), but no change in the level of SP release.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differential release of substance P and somatostatin in the rat spinal cord in response to noxious cold and heat; effect of dynorphin A(1-17). 169 Feb 93

Guanine nucleotide binding proteins (G proteins) sensitive to pertussis toxin (PTX) mediate the muscarinic receptor responses in several tissues. Therefore, the present study sought to investigate whether smooth muscle contractions and/or endothelium-dependent relaxations in response to acetylcholine (ACh) and other agonists were sensitive to PTX. In endothelium-denuded rabbit pulmonary artery rings, ACh, clonidine and serotonin produced concentration-dependent contractions which were markedly inhibited in nominally Ca+(+)-free medium and abolished in the presence of ethylene glycol bis (beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (0.2 mM). In endothelium-denuded arterial rings obtained from rabbits treated in vivo with PTX (5 micrograms/kg i.v., 5 days before sacrifice) maximum contractions to ACh, clonidine and serotonin were inhibited by 77, 67 and 35%, respectively. Contractions induced with KCl (10-40 mM) were also abolished in Ca+(+)-free medium, but they were not affected by PTX. Endothelium-dependent relaxations of phenylephrine-contracted pulmonary arteries in response to ACh adenosine triphosphate and substance P were also reduced or abolished upon removal of extracellular Ca++. However, the endothelium-dependent relaxations were not affected by PTX. These data demonstrate that contractions of pulmonary arterial smooth muscle cells after stimulation through muscarinic receptors, alpha adrenoceptors and serotonin receptors require the influx of extracellular Ca++. This receptor-stimulated Ca++ influx is likely to be regulated by a PTX-sensitive G protein. Also, the induction of release of relaxing factor from endothelial cells of the pulmonary artery via muscarinic, purinergic or substance P receptors requires extracellular Ca++. However, in these cells, a different mode of signal transduction, insensitive to PTX, seems to be involved.
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PMID:Pertussis toxin inhibits contractions but not endothelium-dependent relaxations of rabbit pulmonary artery in response to acetylcholine and other agonists. 215 2

The undecapeptide substance P (SP) is contained in enterochromaffin cells and circulates in high concentrations in patients with carcinoid syndrome. We have previously reported that elevated SP levels, simulating those reported in patients with carcinoid syndrome, induce profound changes in intestinal water and electrolyte secretion, motility, and blood flow in a canine model. The purpose of this study was to attempt to block the effects of circulating carcinoid levels of SP on intestinal secretion and motility with the calcium channel blocker verapamil. In five dogs a chronic proximal jejunal Thiry-Vella loop was constructed, and after a 2-week recovery the loops were perfused with an isotonic test solution containing 14C-polyethylene glycol as a volume marker. Motor activity was measured by changes in intraluminal pressure and a motility index was calculated with computer-assisted planimetry and expressed as square millimeters per 5 minutes. After a 30-minute baseline period, SP was infused at 50 ng/kg/min for 90 minutes. SP circulating levels rose from a baseline of 6.2 +/- 1.3 pg/ml to a peak of 93.3 +/- 3.1 pg/ml during this infusion. Thirty minutes after the start of this SP infusion, a simultaneous infusion of verapamil (5.0 micrograms/kg/min) was begun at a separate site. During SP infusion there was a significant secretory response of water (-48 +/- 12 microliters/min), Na+ (-7.7 +/- 2.5 microEq/min), Cl- (-8.8 +/- 2.7 microEq/min) and K+ (-0.57 +/- 0.14 microEq/min), and hypermotility (motility index: 1479 +/- 138 mm2/5 min). When verapamil was added a reversal of secretion to net absorption was observed (water: + 116.9 +/- 15.6 microliter/min; Na+: + 13.8 +/- 2.1 microEq/min; Cl-: + 5.5 +/- 2 microEq/min; K+: + 0.38 +/- 0.9 microEq/min) (p less than 0.05). In addition, there was a reduction in motility (motility index: 853 +/- 92 mm2/5 min; p less than 0.05). These results confirm that SP has profound effects on both intestinal motility and secretion and that calcium channel blockade reduces these effects significantly.
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PMID:Verapamil inhibition of the intestinal effects of substance P. 241 Sep 86

This study was initiated to evaluate the effect of luminally administered serotonin (5-hydroxytryptamine) and substance P on jejunal handling of water and electrolytes. Five dogs with chronic cannulated jejunal Thiry-Vella loops were studied. The isolated jejunal segments were perfused at 2 ml/min for 2 hours with an isosmotic, isothermic perfusate containing labeled polyethylene glycol for recovery calculation. Fluxes of water and sodium, chloride, and potassium were calculated during 30 minute baseline, 60 minute study, and 30 minute recovery periods. Substance P was administered intraluminally at 25 pg/ml, whereas serotonin was perfused at 600 ng/ml. Neither hormone was absorbed into the portal circulation. Intraluminal serotonin converted absorption to secretion of water from 43 +/- 23 to -105 +/- 25 microliters/min, sodium from 7.3 +/- 3.1 to -15.7 +/- 4.1 microEq/min, chloride from 4.4 +/- 3.4 to -16.4 +/- 3 microEq/min, and potassium from 0.16 +/- 0.20 to -0.86 +/- 0.17 microEq/min. Secretion ceased on cessation of serotonin perfusion. Substance P perfusion induced secretion of chloride (3.6 +/- 1.9 to -9.2 +/- 2.9 microEq/min) but only significantly decreased absorption of water (73 +/- 13 to 13 +/- 21 microliters/min) and sodium (8.1 +/- 1.9 to 0.2 +/- 3.1 microEq/min); in contrast, there was no significant change in jejunal handling of potassium.
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PMID:Effect of luminally administered serotonin and substance P on jejunal handling of water and electrolytes. 241 2

Calcium plays a central role in modulating many physiologic events. We have investigated the role of calcium channel blockade in the control of basal (n = 6)- and substance P-stimulated (n = 6) intestinal transport in the isolated perfused rabbit ileum. Twenty-centimeter segments of ileum, harvested from New Zealand rabbits, were arterially perfused at 1.5 ml/min with an oxygenated modified Krebs buffer solution containing washed human red cells (Hct = 15-20%) and 2.5 mM Ca2+. The intestinal lumen was perfused at 2 ml/min with an isotonic solution containing 1.2 mM Ca2+ and [14C]PEG as a nonabsorbable volume marker. The infusion of verapamil (1 microgram/min) significantly reduced (P less than 0.05) the basal secretion of H2O, and Cl-. Verapamil prevented the secretory effect of substance P infused at 0.25 microgram/min. Intraarterial verapamil had no effect on vascular perfusion pressure. These data indicate that calcium channel blockade has significant effects on basal- and substance P-stimulated intestinal secretion and suggest that transmembrane calcium fluxes function as major determinants of basal- and secretagogue-stimulated intestinal transport.
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PMID:The effect of calcium channel blockade on basal- and substance P-induced intestinal secretion. 245 37

The actions of serotonin and substance P have been examined with use of an isolated, vascularly perfused rabbit ileal preparation. The vascular perfusate was composed of a modified Krebs' buffer solution that contained washed human red blood cells (hematocrit, 15% to 20%) and 3% albumin, with no added hormones or peptides. Ileal blood flow was held constant at 49.3 +/- 3.1 ml/min per 100 gm wet weight of intestine. Net intestinal water and electrolyte fluxes were calculated by means of an isosmotic buffer that contained carbon-14 polyethylene glycol as a nonabsorbable volume marker. Viability of this isolated perfused ileal preparation was confirmed on the basis of light microscopy, oxygen consumption, and transmucosal potential difference measurements. Control experiments, without exogenous hormone infusion, resulted in a stable preparation with a basal secretory state. Intra-arterial serotonin at 2.5 micrograms/min (n = 10) significantly stimulated secretion of H2O, Na+, and Cl- (p less than 0.01). Intra-arterial substance P at 2.5 x 10(-1) micrograms/min (n = 7) significantly increased the secretion of H2O, Na+, and Cl- (p less than 0.02). The dose of serotonin was designed to yield serotonin levels that resembled those found circulating in patients with carcinoid syndrome. These data indicate that serotonin and substance P are potent secretagogues in a mammalian system, independent of their effect on mesenteric blood flow and in the absence of extra-intestinal hormonal and neural influences.
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PMID:Serotonin and substance P stimulate intestinal secretion in the isolated perfused ileum. 246 83

The location of [125I]iodotyrosyl gastrin-releasing peptide-binding sites in the rat fundic mucosa was studied. Peptide specificity was demonstrated by competitive binding studies using the addition of a large amount of cold gastrin-releasing peptide or substance P. Autoradiography of the stomach tissue was carried out by freeze-drying, embedding in Epon, wet-sectioning with ethylene glycol, and dry-mounting the emulsion film by the wire-loop method to prevent loss of the labeled substance. Specific binding sites of gastrin-releasing peptide were found on D cells, surface mucus cells, and parietal cells, whereas few binding sites were seen on the chief or mucus neck cells.
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PMID:Autoradiographic demonstration of gastrin-releasing peptide-binding sites in the rat gastric mucosa. 283 Nov 6

Intracerebroventricular (i.c.v.) injection of kassinin produced a prompt and copious drinking response at doses of 10-1000 ng/pigeon, in the absence of other behavioural alterations or of changes in core temperature. Neurokinin A and B evoked drinking, but they were respectively 10 and 100 times less potent than kassinin. Intraperitoneal injection of kassinin elicited drinking, but at doses about 1000 X larger than the i.c.v. ones. The angiotensin antagonist [Sar1, Leu8]angiotensin II did not reduce drinking induced by i.c.v. kassinin, suggesting that its effect is not due to interaction with the central renin-angiotensin system. Moreover, the effect is apparently independent of the mechanisms controlling hypovolaemic and hyperosmotic thirst since exact additivity was found in the dipsogenic response when i.c.v. kassinin was administered in the presence of a hypovolaemic (subcutaneous (s.c.), polyethylene glycol) or hyperosmotic (s.c. hypertonic NaCl) dipsogenic stimulus. The present findings show that kassinin, neurokinin A and B share with the tachykinins already tested (eledoisin, physalaemin, substance P) a common dipsogenic action in pigeons. However, marked differences exist in their dipsogenic potency. This order of potency, eledoisin = kassinin = physalaemin greater than neurokinin A = substance P greater than neurokinin B, is not consistent with the tachykinin receptor subtypes so far proposed.
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PMID:Effect of kassinin, neurokinin A and neurokinin B on drinking behaviour in the pigeon. 303 52

The human neurokinin-1 receptor has been expressed in insect cells using a recombinant baculovirus. The expression level is about 10 times higher than that obtained in mammalian cells. The recombinant receptor was solubilized with CHAPS, and a PEG precipitation procedure was shown to be effective in regaining high affinity substance P binding. This system should allow large scale purification of the human neurokinin-1 receptor.
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PMID:Expression and solubilization of a recombinant human neurokinin-1 receptor in insect cells. 815 83

In C6-2B rat glioma cells, agonist-stimulated cAMP accumulation is potently inhibited after the stimulation of endogenous bradykinin receptors or stably transfected substance K receptors, coupled to phosphatidylinositol hydrolysis. In the present report, pharmacological tools were used to selectively stimulate either protein kinase C or Ca2+, the two final effectors activated upon phosphatidylinositol hydrolysis, and their role in the inhibition of the C6-2B cell cAMP signaling pathway was investigated. Activation of protein kinase C by an acute treatment with phorbol 12-myristate 13-acetate or L-alpha-1-oleoyl-2-acetyl-sn-3-glycerol did not reduce, but rather enhanced, the cAMP accumulation elicited by forskolin, a direct activator of adenylyl cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1]. This effect was antagonized by the protein kinase inhibitor H-7 and mimicked by the protein phosphatase inhibitor okadaic acid. Thapsigargin, a selective microsomal Ca(2+)-ATPase inhibitor, evoked a sustained increase in the intracellular free Ca2+ concentration, with an EC50 of 24.8 +/- 4.3 nM, and inhibited the cAMP accumulation induced by the beta-adrenergic receptor agonist isoproterenol with comparable potency (IC50 = 19.3 +/- 0.2 nM), strongly suggesting a causal relationship between the two phenomena. The inhibition by thapsigargin of isoproterenol- or forskolin-stimulated cAMP accumulation was not affected by pertussis toxin or down-regulation or inhibition of protein kinase C. Dantrolene, a blocker of Ca2+ release from intracellular stores, antagonized 1) the Ca2+ transient in response to thapsigargin and substance K and 2) the inhibitory effect of these compounds on isoproterenol- or forskolin-induced cAMP accumulation. Moreover, sequestration of intracellular Ca2+ with the cell-permeable Ca2+ chelator ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid acetoxymethyl ester abolished the cAMP inhibition mediated by thapsigargin. Finally, isoproterenol- or forskolin-stimulated adenylyl cyclase activity in digitonin-permeabilized cells was not affected by either thapsigargin or substance K. These data provide compelling evidence that increases in intracellular free Ca2+ concentration without activation of protein kinase C suffice and are responsible for the inhibition of cAMP accumulation in C6-2B cells.
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PMID:Ca2+ inhibition of beta-adrenergic receptor- and forskolin-stimulated cAMP accumulation in C6-2B rat glioma cells is independent of protein kinase C. 838 3


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