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 present study was designed to examine some of the pharmacological properties of venom from the stonefish (Synanceja trachynis), with particular reference to the presence in the venom of pain-producing/enhancing substances. Stonefish venom (1-6 micrograms/ml) produced concentration-dependent contractile responses in guinea-pig isolated ileum. No tachyphylaxis, or reduction in responses with time, was observed to venom (3 micrograms/ml) in ileum. The response to venom (3 micrograms/ml) was not significantly affected by the histamine antagonist mepyramine (0.5 microM), or a preceding anaphylactic response. Mecamylamine, 5HT-desensitization or EXP3174 failed to have any significant effect on responses to venom (3 micrograms/ml). Responses to venom (3 micrograms/ml) were significantly inhibited by the cyclooxygenase inhibitor indomethacin (5 microM), the leukotriene D4 receptor antagonist FLP55712 (1 microM), the thromboxane A2 receptor antagonist GR32191B (1 microM), the muscarinic receptor antagonist atropine (10 nM) and the neurokinin-1 receptor antagonist CP96345 (0.1 microM). Venom (6 micrograms/ml) produced contractile responses in the rat isolated vas deferens which were abolished by the alpha 1-adrenoceptor antagonist prazosin (0.3 microM) and significantly potentiated by the neuronal uptake inhibitor DMI (1 microM). However, noradrenergic transmitter depletion with reserpine (5 mg/kg, i.p.) did not significantly inhibit responses to venom (6 micrograms/ml). Histamine fluorometric and phospholipase A2 assays failed to detect significant quantities of either substance in the venom. These results suggest that stonefish venom may cause the release of acetylcholine, substance P, and cyclooxygenase products, or contain components which act at these receptors. The venom also appears to contain a component which is a substrate for neuronal uptake and has a direct action at alpha 1-adrenoceptors.
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PMID:Pharmacological studies of stonefish (Synanceja trachynis) venom. 784 90

From the bronchioles of guinea-pigs, preparations were isolated for registration of perfused pressure on electrical field stimulation (EFS) and by application of drugs. The perfused bronchioles contracted when EFS was applied in the presence of atropine and phentolamine suggesting a non-adrenergic non-cholinergic (NANC) response. (R)-alpha-Methylhistamine (methylhistamine), a selective H3 agonist, reduced the NANC bronchoconstrictor response in a concentration-dependent manner. beta-Adrenoceptors, muscarinic and histamine (H1 and H2 receptor) antagonists, epithelial removal and cyclooxygenase inhibition had no effect on this inhibitory action of methylhistamine whereas the H3 antagonist, thioperamide, reduced the inhibitory effect of methylhistamine with a Ki value of 2.98 x 10(-9) M. Methylhistamine had no effect on the concentration-dependent contraction induced by exogenous substance P and neurokinin A, demonstrating that an H3 receptor might inhibit the release of transmitter from NANC nerves on guinea-pig perfused bronchioles in-vitro.
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PMID:Effect of an histaminergic H3 agonist on the non-adrenergic non-cholinergic contraction in guinea-pig perfused bronchioles. 790 36

Calcitonin (CT) is a polypeptide hormone produced in the thyroid gland that regulates, blood calcium levels and bone calcium metabolism. The unexpected finding of binding sites for calcitonin in several areas of the brain oriented attention to activities of CT in the central nervous system and also to its antinociceptive action. The first report of this last effect was in 1975, and the many different experimental and clinical data on this topic reported since then are reviewed here. The heterogenous findings have been organized according to the logical classification of animal and human studies. For each of these headings, subheadings such as acute and chronic pain, different kinds of administration and different procedures used to record the results, are considered. The several proposed mechanisms of action, involving serotoninergic, catecholaminergic, Ca2+ fluxes, protein phosphorylation, beta-endorphin production, cyclooxygenase inhibition and histamine interference are also reviewed. Calcitonin, neurotensin, substance P, VIP and, recently, CGRP are some of the non-opioid peptides that have been reported to interfere with pain and that open up a new, alternative way of investigating antinociceptive drugs different than opioid or opioid-like agents. An examination of the state-of-investigation of calcitonin's antinociceptive activity in the last 17 years shows that many experimental studies indicate the existence of this effect, including studies in humans, and this opens up perspectives for therapy with a new class of antinociceptive agents.
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PMID:Calcitonin and its antinociceptive activity: animal and human investigations 1975-1992. 794 19

We have investigated the contractile effect of bradykinin (BK) in guinea pig lung in vitro. BK induces a dose-related contraction of lung parenchymal strips which is increased significantly in the presence of 10(-5) M captopril (an angiotensin converting enzyme inhibitor) or 10(-5) M DL-thiorphan (a neutral endopeptidase inhibitor). The kininase I inhibitor, DL-2-mercaptomethyl-3-guanidino-ethylthiopropionic acid (MGTPA), has no effect on the BK-induced contraction. BK is more potent in contracting parenchymal lung strips than other contractile agents (histamine, carbachol and substance P), however the BK-induced maximal contraction is lower than those obtained with histamine and carbachol. The B1 agonist, des-Arg9-BK, does not contract lung parenchymal strips. The new BK B2 receptor antagonists (Hoe 140, NPC 17731 and NPC 17761), which possess binding affinities in the nanomolar range, inhibit the BK-induced contractile response in a dose-dependent manner. The BK-induced contraction was unaffected by propranolol, atropine, tetrodotoxin, capsaicin pre-treatment, triprolidine, methysergide, Ro 19-3704 and N omega-nitro-L-arginine-methyl-ester (L-NAME), excluding the involvement of nervous pathways, preformed mast cell mediators, platelet-activating factor and nitric oxide. However, indomethacin, a cyclooxygenase inhibitor, AA-861, a 5-lipoxygenase inhibitor, and furegrelate, a thromboxane A2 synthase inhibitor, decreased the contractile response to BK, suggesting that both cyclooxygenase and 5-lipoxygenase products are involved in this contraction.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Bradykinin-induced contraction of guinea pig lung in vitro. 799 Sep 78

The mechanisms and receptor subtype mediating vasodilator responses to bradykinin were investigated in the hindquarters vascular bed of the cat under constant flow conditions. Intraarterial injections of bradykinin in doses of 10-1,000 ng into the hindquarters vascular bed caused dose-related decreases in perfusion pressure that were inhibited by Hoe-140, a bradykinin B2-receptor antagonist. Injections of des-Arg9-bradykinin (in doses 10-fold higher than for bradykinin) caused smaller dose-related decreases in hindquarters perfusion pressure that were not blocked by Hoe-140. Administration of atropine, glibenclamide, or cyclooxygenase inhibitors did not alter vasodilator responses to bradykinin, suggesting that activation of muscarinic receptors, ATP-sensitive K+ channels, or prostaglandin release is not involved in the response to the peptide. Administration of N omega-nitro-L-arginine and its methyl ester reduced vasodilator responses to bradykinin, acetylcholine, and substance P, whereas responses to endothelium-independent vasodilator agents were not attenuated. Decreases in systemic arterial pressure and in hindquarters perfusion pressure in response to bradykinin were enhanced by the angiotensin-converting enzyme inhibitors captopril and enalaprilat. These results suggest that hindquarters vasodilator responses to bradykinin are mediated by activation of kinin B2 receptors and in part by the release of nitric oxide. These data also suggest the presence of bradykinin B1 receptors, mediating vasodilation in the hindquarters vascular bed. These results indicate that bradykinin is rapidly inactivated by angiotensin-converting enzyme in the lung and in the hindquarters vascular bed of the cat.
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PMID:Analysis of responses to bradykinin: effects of Hoe-140 in the hindquarters vascular bed of the cat. 806 39

Our previous studies have shown that the inhibition of neutral endopeptidase, an enzyme which degrades tachykinins, increases anaphylactic contraction of guinea pig tracheal smooth muscle. It was suggested that anaphylactic release of tachykinin-like substances is likely to be responsible for the observed increases in tracheal contractions. To obtain additional information on the mechanisms responsible for anaphylactic release of tachykinins in guinea pig trachea, we examined the effects of phosphoramidon, an inhibitor of neutral endopeptidase, on contractile response to antigen after preincubation with the selective 5-lipoxygenase inhibitor AA-861. AA-861 (5 microM) significantly reduced ovalbumin-induced contraction, although the effect was not constant. A marked spontaneous increase in contraction was observed. Phosphoramidon (10 microM) produced significant increase of this contraction (27% after 30 min, and 33% after 45 min). The addition of H1-histamine receptor antagonist (diphenhydramine HCl, 10 microM) produced additional inhibition of the initial phase of antigen-induced contraction, while its later phase, apart from a spontaneous increment in magnitude, remained similar. Phosphoramidon (10 microM) increased the contraction by 26% after 30 min, and by 34% after 45 min. Since the effects of histamine and 5-lipoxygenase pathway products were prevented, we hypothesize that cyclooxygenase pathway products are responsible for the phosphoramidon-dependent increase in antigen-induced contraction. In accordance with previously reported ineffectiveness of contractile prostaglandins, we suggest that the relaxant prostaglandins are most important in mediating the release of tachykinins during the immediate hypersensitivity reaction in guinea pig trachea.
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PMID:Phosphoramidon modulates effects of the 5-lipoxygenase inhibition on anaphylactic contraction of the guinea pig trachea. 811 Dec 48

Guinea pigs mechanically hyperventilated with dry gas exhibit hyperpnea-induced bronchoconstriction (HIB) and hyperpnea-induced bronchovascular hyperpermeability (HIBVH). Tachykinins released from airway C-fiber neurons are the central mediators of guinea pig HIB but play only a contributory role in HIBVH. Recent studies suggest that eicosanoid mediators can provoke bronchoconstriction and bronchovascular hyperpermeability, are released by dry gas hyperpnea, and can themselves elicit or modulate tachykinin release. We therefore hypothesized that eicosanoids may participate in HIB and/or HIBVH. To test these hypotheses, we analyzed respiratory system resistance changes and Evans blue-labeled albumin extravasation into the airways of 60 tracheostomized and mechanically ventilated guinea pigs. Animals were subjected to 10 min of isocapnic dry gas hyperpnea or to quiet breathing of humidified gas and received as pretreatment either piroxicam, a cyclooxygenase (CO) inhibitor; A-63162, a 5-lipoxygenase (5-LO) inhibitor; BW-755c, a combined CO and 5-LO inhibitor; ICI-198,615, a leukotriene D4 receptor antagonist; or no drug. HIB was substantially (50-80%) reduced by each of the four eicosanoid-modulating drugs. In contrast, HIBVH was reduced only by BW-755c, and this effect occurred only within the extrapulmonary airways (42% reduction). These data indicate that both CO and 5-LO products, including leukotriene D4, participate in the pathogenesis of HIB but that, like tachykinins, they play only a small contributory role in HIBVH. Together with our previous demonstration that sensory neuropeptide release is critical for the occurrence of HIB, we conclude that the roles of eicosanoids and tachykinins in guinea pig HIB are interdependent.
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PMID:Role of eicosanoids in hyperpnea-induced airway responses in guinea pigs. 812 4

Recent studies have shown that intrathecal NSAIDs can produce a significant, dose-dependent reduction in the second phase of the formalin response and block thermal hyperalgesia induced by spinally injected N-methyl-D-aspartate and substance P. These observations support the body of literature that indicate that sustained small fiber input yields a hyperalgesia through activation of spinal NMDA and NK1 receptors and that in turn a portion of this action is mediated by the spinal release of cyclooxygenase products.
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PMID:Spinal actions of NSAIDS in blocking spinally mediated hyperalgesia: the role of cyclooxygenase products. 831 44

Substance P (SP), fibroblast growth factor (FGF), and epidermal growth factor (EGF) are mitogens for fibroblasts. EGF acts as a progression factor, whereas FGF and SP have competence factor activity. The ability of eicosanoids to regulate proliferation of fibroblasts and the increased production of prostaglandins by fibroblasts in response to the growth factors, led us to investigate the involvement of cyclooxygenase-dependent arachidonic acid metabolites in the mitogenic response of serum-starved human skin fibroblasts to SP, FGF, and EGF. We tested the interaction of a submaximal concentration of SP(10(-9)M) with baFGF(40 micrograms/ml) and EGF(0.01 microgram/ml) both on fibroblast proliferation and release of arachidonic acid metabolites. A combination of SP and EGF synergistically stimulated fibroblast proliferation and prostaglandin E2 release, whereas addition of SP to FGF-containing cultures did not affect cell growth. Inhibition of cyclooxygenase by acetylsalicylic acid augmented the growth response of fibroblasts to all: SP, FGF, and EGF. In the presence of acetylsalicylic acid, SP combined with FGF enhanced fibroblasts proliferation, whereas a combination with EGF inhibited cellular growth with respect to growth induced by EGF alone. Thus, interactions of SP with FGF and EGF differently affected the mitogenic response depending on the formation of arachidonic acid metabolites. The findings indicate that eicosanoids may be important mediators of competence and progression factor activities that may determine the effects of substance P on fibroblast proliferation in a cytokine network.
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PMID:Interaction of substance P with epidermal growth factor and fibroblast growth factor in cyclooxygenase-dependent proliferation of human skin fibroblasts. 860 Jan 64

Nerve growth factor (NGF) is known to produce hyperalgesia as well as to stimulate synthesis of neuropeptides in dorsal root ganglia (DRG). In the present study, we wanted to determine the effects of local NGF administration and assess to which extent mast cell-dependent factors are mediating NGF responses. Rats received 1 daily unilateral intraplantar injection for 3 days. Local edema (days 1-3), changes in thermal nociceptive threshold (days 1-4), and the content of calcitonin gene-related peptide (CGRP) and substance P (SP) in the sciatic nerve (day 4), were determined. NGF injection caused edema which was absent in rats pretreated with compound 48/80 as well as in rats treated neonatally with capsaicin ('capsaicin denervation'). NGF-induced edema was not reduced by the neurokinin-1 receptor antagonist SR140333, but attenuated by the CGRP receptor antagonist CGRP[8-37]. On each day, NGF injection caused a decrease in thermal nociceptive threshold which lasted for less than 3 h. Capsaicin denervation, but not treatment with indomethacin, abolished NGF-induced thermal hyperalgesia. Treatment with compound 48/80 attenuated hyperalgesia produced by the first, but not by subsequent, NGF injections. On day 4, 24 h after the last of 3 NGF injections, thermal nociceptive threshold was not different from control values, but at that time, CGRP and SP were elevated in the sciatic nerve. We suggest therefore that NGF-induced local edema was caused by mast cell-derived vasoactive compounds which act together with afferent neuron-derived CGRP to increase vascular permeability. NGF-induced thermal hyperalgesia most likely was caused by an increased sensitivity of peripheral endings of capsaicin sensitive afferents. This effect of NGF was not mediated by products of the cyclooxygenase pathway, and was also observed in mast cell-depleted rats.
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PMID:Intraplantar injection of nerve growth factor into the rat hind paw: local edema and effects on thermal nociceptive threshold. 874 Jun 10


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