Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Capsaicin (1 microM) produced, after an initial contraction, a depression of the field stimulation-induced contraction of the guinea-pig isolated ileal longitudinal muscle. Both effects exhibited prompt desensitization, indicating the involvement of a specific action on sensory nerves. The initial contraction was inhibited by [D-Pro4,D-Trp7,9,Phe11]SP-(4-11), a substance P (SP) antagonist, which did not affect the inhibitory component of the response. Incubation of the strips with antiCGRP (CGRP = calcitonin gene-related peptide) serum did not modify the amplitude of the capsaicin-induced contraction but inhibited the twitch depression induced by capsaicin. AntiCGRP serum blocked the effects of exogenous CGRP but not the inhibitory response induced by baclofen. These findings provide evidence that the release of several neuropeptides from sensory nerves determines the visceromotor response to capsaicin in this preparation. In particular, a CGRP-like peptide could be responsible for the inhibitory phase which follows the initial contraction which is due to release of SP and/or related peptides.
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PMID:Several neuropeptides determine the visceromotor response to capsaicin in the guinea-pig isolated ileal longitudinal muscle. 245 31

1. The ability of capsazepine, a recently developed capsaicin receptor antagonist, to prevent the effects of capsaicin on the rat isolated urinary bladder (contraction) and vas deferens (inhibition of electrically-evoked twitches) was compared to that of ruthenium red, a dye which behaves as a functional antagonist of capsaicin. 2. In the rat bladder, capsazepine (3-30 microM) produced a concentration-dependent rightward shift of the curve to capsaicin without any significant depression of the maximal response to the agonist. By contrast, ruthenium red (10-30 microM) produced a non-competitive type of antagonism, characterized by marked depression of the maximal response attainable. Similar findings were obtained in the rat isolated vas deferens in which capsazepine (10 microM) produced a rightward shift of the curve to capsaicin while ruthenium red (3 microM) depressed the maximal response to the agonist. 3. At the concentrations used to block the effect of capsaicin, neither capsazepine nor ruthenium red affected the contractile response of the rat urinary bladder produced by either neurokinin A or electrical field stimulation or the twitch inhibition produced by rat alpha-calcitonin gene-related peptide (alpha CGRP) in the vas deferens. 4. These findings provide additional evidence that both capsazepine and ruthenium red are valuable tools for exploration of the function of capsaicin-sensitive primary afferent neurones. The antagonism of the action of capsaicin by capsazepine is entirely consistent with the proposed interaction of this substance with a vanilloid receptor located on primary afferents, while the action of ruthenium red apparently involves a more complex, non-competitive antagonism.
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PMID:A comparison of capsazepine and ruthenium red as capsaicin antagonists in the rat isolated urinary bladder and vas deferens. 768 39

We have investigated the ability of human alpha CGRP (CGRP) to inhibit the electrically-evoked myogenic contractions of the guinea-pig ureter, in comparison with the K channel opener, cromakalim, and the adenylate cyclase activator, forskolin. CGRP (0.1 nM-0.1 microM) produced a concentration-dependent inhibition of the evoked contractions; its action was prevented by the CGRP receptor antagonist, CGRP(8-37) (1 microM), while it was unaffected by the nitric oxide (NO) synthase inhibitor, L-nitroarginine (30 microM). The effect of CGRP was antagonized in a noncompetitive manner (depression of Emax, no change in EC50) by glibenclamide (1-10 microM), a blocker of ATP-sensitive potassium channels (KATP). A substantial fraction of the inhibitory effect of CGRP was glibenclamide-resistant, however. Glibenclamide also blocked the inhibitory action of cromakalim (0.1-10 microM) without affecting the inhibition produced by forskolin (0.1-30 microM). When tested in a low-K medium (extracellular K reduced from 5.9 to 1.2 mM), the inhibitory effects of CGRP, cromakalim and forskolin were enhanced. The inhibitory effect of forskolin was partly antagonized by glibenclamide when tested in a low-K medium. CGRP (0.1 microM), cromakalim (3 microM) and forskolin (10 microM) inhibited the contractile response to KCl (80 mM), which is characterized by a distinct phasic and tonic component: cromakalim selectively inhibited the phasic response to KCl with CGRP and forskolin inhibited both components. The inhibitory effect of CGRP on the phasic contraction to KCl was partly glibenclamide-(1 microM) sensitive, while that on the tonic contraction was glibenclamide-resistant. The inhibitory action of forskolin on both components of the response to KCl was unchanged by glibenclamide.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Multiple mechanisms in the smooth muscle relaxant action of calcitonin gene-related peptide (CGRP) in the guinea-pig ureter. 787 Jan 93

Galanin (GAL)-immunoreactive axon terminals on motor endplates of the esophageal striated muscles were demonstrated in mice, guinea-pigs and rats. The GAL-terminals innervated 33% of AChE-reactive motor endplates in mice and 6% of those in guinea-pigs. Double immunostaining revealed that separate GAL- and CGRP-positive terminals were localized within the same motor endplates in mice and rats. The GAL and CGRP terminals had different morphologies. No CGRP-immunoreactivity was found on motor endplates of the guinea-pig esophagus. Double immunostaining in rats showed that 68% of motor endplates with CGRP-nerve terminals were also supplied by GAL-nerve terminals, suggesting that the majority of esophageal striated muscles receive a dual innervation of GAL-and CGRP/ACh-containing terminals. By immuno-electronmicroscopy in the rat esophagus. GAL-immunoreaction was found in a small type of nerve terminals that possessed many large cored vesicles (90-130 nm) with intense immunoreaction. Larger GAL-negative nerve terminals with a cluster of small clear vesicle (40-50 nm), which seemed to be ACh-containing nerve terminals, were adjacent to a depression or slight protrusion of the sarcolemma and well-developed folds in the muscle fibers. At the motor endplates, the GAL-positive terminals made a synaptic contact via basement membrane with the sarcolemma of the muscle fibers, which was characterized by post-synaptic intense electron density. In most of all situations, in which the GAL-positive terminals and GAL-negative or -positive terminals were adjacent to each other and were also apposed to the striated muscles, the terminals were separated by attenuated sheet- or tongue-like cytoplasmic processes that appeared to originate from Schwann cells. Thus, the GAL-nerve terminals seem to provide a direct innervation of the striated muscle fibers rather than innervating the ACh-containing motor nerve terminals adjacent to the GAL-terminals.
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PMID:Galanin-containing nerve terminals that are involved in a dual innervation of the striated muscles of the rat esophagus. 889 24

This work includes results on chronotropic, inotropic and lusitropic changes induced by capsaicin on isolated rat atria. As regards spontaneous frequency, it was stimulated from 10(-9) M up to 7 x 10(-7) M of capsaicin. A simultaneous depression in developed force (F) showed a significant correlation with this positive chronotropic effect up to 7 x 10(-8) M of capsaicin, which is the result of the negative staircase phenomenon in the rat heart. The correlation was lost at 2 and 7 x 10(-7) M of capsaicin since in spite of the sustained increase in atrial rate the decrease in F was reversed and then depressed again at 2 and 7 x 10(-6) M of capsaicin without changes in frequency. A concentration of capsaicin that overcome the negative staircase phenomenon, 5 x 10(-7) M, was tested as unique dose resulting in stimulation of the chronotropic, inotropic and lusitropic states of the atria. Percentual differences with respect to control values were maximal after 1-3 minutes for frequency (10 +/- 3%), F (29 +/- 4%), maximal velocity of force development (+F = 50 +/- 12%) (in all cases +F and -F bold indicates +F and -F, respectively), and maximal velocity of relaxation (-F = 64 +/- 13%); a positive lusitropic effect was significant after 8-10 minutes (+F/-F = 17 +/- 7%). Capsaicin did not affect the rat atria in the presence of 10(-6) M of ruthenium red, a blocker of capsaicin activation of sensory nerves, indicating that the stimulatory effects were entirely mediated by the release of neurotransmitters and that this concentration of capsaicin was not deleterous "per se". Capsaicin elicited similar inotropic responses in electrically driven isolated atria (+F = 41 +/- 9%) but the positive lusitropic effect was lost suggesting that capsaicin-induced increases in -F are limited at a frequency higher than the spontaneous frequency (11 +/- 6 vs. 32 +/- 4%, respectively). 10(-6) M of CGRP8-37, an antagonist of CGRP1 receptors, suppress the stimulatory effects of capsaicin on atrial contraction. In summary, atrial rate as compared to atrial contraction is more sensitive to the neurotransmitter released by capsaicin, which results in mechanical effects expressing the negative staircase phenomenon in the rat at low concentrations of capsaicin. The positive chronotropic, inotropic and lusitropic responses elicited by capsaicin are mediated by the release of neurotransmitters from sensory fibbers and no deletereous effects of capsaicin "per se" became evident when the release of neuropeptides was prevented. Atrial contraction was depressed at higher capsaicin concentrations than the one showing stimulatory effects. Stimulation of atrial contractility is mediated by activation of CGRP receptors.
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PMID:Chronotropic, inotropic and lusitropic effects of capsaicin on isolated rat atria. 969 77

Membrane metalloendopeptidase EC 3.4.24.11 (Enkephalinase, neutral endopeptidase, NEP) is a cellular ectoenzyme, immunophenotypically identified as the leukocyte cluster of differentiation CD10 or CALLA (common acute lymphoblastic leukemia antigen). Immunological, biochemical and molecular biology techniques have identified tis cell membrane feature in various organs: brain, cardiovascular system, lung, placenta, kidney etc. The CD10 immunophenotype is a common feature of lymphoblasts in acute lymphoid leukemia not expressing the T- or B-markers. The enzymatic activity of CD10/NEP possibly influences normal lymphocyte ontogeny by proteolytic cleavage of the regulatory peptides. The substrates of CD10/NEP in the kidneys are (see the list of abbreviations) ANP, adrenomedullin and PAMP; in the brain, the substrates are enkephalins and oxytocin; in the lung, bombesin, BLP, GRP, neuromedin C, substance P and neurokinin A; in the cardiovascular system, angiotenisin II, bradykinin and CGRP; in the gut, VIP; on the neutrophil membrane, fMLP etc. Some substrates are not strictly tissue-specific, e.g. substance P. Preclinical and clinical trials explore possibilities of therapeutic application of the inhibitors of neutral endopeptidase, such as thiorphan in the management of pain, diarrhoea, depression, arterial hypertension and asthma. Other possibilities of application include the treatment of hyalinomembranous disease and prevention of neurotoxicosis in tetanus and botulism.
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PMID:[Membrane metalloendopeptidase (CD10/CALLA): distribution, physiologic and pathophysiologic functions and its inhibitors]. 974 92

The pathophysiology of migraine is not yet fully understood. The most important structures involved seem to be the central nervous system (cortex and brain stem), the trigeminovascular system and related cranial arteries, other autonomic fibres innervating such vessels, and various local vasoactive agents, including SP, CGRP, NO, VIP, NPY, ACh, NA, NKA, among others. The spreading depression phenomenon may explain clinical as well experimental findings in migraine. Its propagation velocity mirrors what is found in clinical aura, it may activate the spinal trigeminal nucleus and may induce CGRP and NO release. Circulatory changes detected with various imaging procedures during migraine also support the pathophysiological role of spreading depression. Three abnormal loci (chromosomes 1 and 19) have been recently found in familial hemiplegic migraine. This produces abnormalities in the voltage-dependent P/Q Ca channel, specific for the central nervous system, which regulates the release of various neurotransmitters, probably including serotonin. It is possible that a channelopathy underlies the pathophysiology of migraine, as in other paroxysmal neurological disorders secondary to membrane hyperexcitability.
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PMID:[Physiopathology of migraine]. 1002 93

Current theories propose that the primary dysfunction in migraine occurs within the CNS and that this evokes changes in blood vessels within pain-producing intracranial meningeal structures that give rise to headache pain. Migraine is now thought of as a neurovascular disorder. It has been proposed that genetic abnormalities may be responsible for altering the response threshold to migraine specific trigger factors in the brain of a migraineur compared to a normal individual. The exact nature of the central dysfunction that is produced in migraineurs is still not clear and may involve spreading depression-like phenomena and activation of brain stem monoaminergic nuclei that are part of the central autonomic, vascular and pain control centers. It is generally thought that local vasodilatation of intracranial extracerebral blood vessels and a consequent stimulation of surrounding trigeminal sensory nervous pain pathways is a key mechanism underlying the generation of headache pain associated with migraine. This activation of the 'trigeminovascular system' is thought to cause the release of vasoactive sensory neuropeptides, especially CGRP, that increase the pain response. The activated trigeminal nerves convey nociceptive information to central neurons in the brain stem trigeminal sensory nuclei that in turn relay the pain signals to higher centers where headache pain is perceived. It has been hypothesized that these central neurons may become sensitized as a migraine attack progresses. The 'triptan' anti-migraine agents (e.g. sumatriptan, rizatriptan, zolmitriptan naratriptan) are serotonergic agonists that have been shown to act selectively by causing vasoconstriction through 5-HT1B receptors that are expressed in human intracranial arteries and by inhibiting nociceptive transmission through an action at 5-HT1D receptors on peripheral trigeminal sensory nerve terminals in the meninges and central terminals in brain stem sensory nuclei. These three complementary sites of action underlie the clinical effectiveness of the 5-HT1B/1D agonists against migraine headache pain and its associated symptoms.
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PMID:Pathophysiology of migraine--new insights. 1056 28

Rat atria is richly innervated by sensory nerve fibers that release CGRP when stimulated either by capsaicin or acid pH. We studied the physiological relevance of acid pH-induced CGRP release on changes in atrial contractility and relaxation produced by lowering the pH. Isolated atria electrically paced at 2.77 Hz were exposed to a 10-minute period of metabolic acidosis (pH=6.73+/-0.01, n=28) after: 1) CGRP release induced by capsaicin 0.5 microM; 2) blockage of CGRP release with ruthenium red (RR) 5 microM; 3) no pretreatment; and 4) CGRP receptor blockage with CGRP(8-37) 1 microM. Contractility and relaxation were significantly less depressed by acid pH when CGRP release was prevented by RR or CGRP receptor activation was blocked by CGRP(8-37). The results suggest that CGRP release and the activation of CGRP receptors may be physiologically involved in contributing to the depression of contractility and relaxation induced by acid pH in rat atria.
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PMID:Influence of calcitonin gene-related peptide release on pH-induced mechanical depression in rat atria. 1169 86

The N-terminal 1-7 fragment of the neuropeptide CGRP inhibits neuronal nicotinic acetylcholine receptors (nAChRs) of rat chromaffin cells. To identify the structural motif responsible for this action, we investigated the effects of shorter CGRP fragments on patch-clamped rat chromaffin cells in culture. CGRP(1-6) evoked no direct change in baseline current or input conductance, but it strongly potentiated inward currents induced by very fast, nondesensitizing applications of nicotine. Potentiation was use independent and present even when coapplied with nicotine. The action of CGRP(1-6) was voltage independent and agonist independent. Because equimolar concentrations of CGRP(1-6) and CGRP(1-7) left nicotine-induced submaximal currents unchanged, these peptides presumably acted via a similar site through which they generated opposite effects. This observation also suggests that a single amino acid deletion could transform a peptide antagonist into a potentiating one. Deleting one amino acid from the COO(-) end of the CGRP(1-6) sequence yielded CGRP(1-5), which retained smaller potentiating activity. Even the CGRP(1-4) fragment possessed slight potentiation, which was lost with CGRP(1-3). CGRP(1-6) preferentially potentiated small over large responses to nicotine. One possibility is that CGRP(1-6) interacted with nAChRs like an allosteric modulator (e.g., physostigmine). Coapplication of enhancing concentrations of physostigmine and CGRP(1-6) led to linear summation of the individual effects, while CGRP(1-6) could partly reverse the depression by a large concentration of physostigmine. These data indicate functionally distinct sites of action for CGRP(1-6) and physostigmine. Potentiation of nicotinic receptors by CGRP(1-6) and its derivatives suggests them to be a new class of molecules enhancing activity mediated by nAChRs.
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PMID:Enhancement of neuronal nicotinic receptor activity of rat chromaffin cells by a novel class of peptides. 1243 99


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