| 1. |
- Bautista, D M, et al.
(author)
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Pungent products from garlic activate the sensory ion channel TRPA1
- 2005
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In: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 102:34, s. 12248-12252
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Journal article (peer-reviewed)abstract
- Garlic belongs to the Allium family of plants that produce organosulfur compounds, such as allicin and diallyl disulfide (DADS), which account for their pungency and spicy aroma. Many health benefits have been ascribed to Allium extracts, including hypotensive and vasorelaxant activities. However, the molecular mechanisms underlying these effects remain unknown. Intriguingly, allicin and DADS share structural similarities with allyl isothiocyanate, the pungent ingredient in wasabi and other mustard plants that induces pain and inflammation by activating TRPA1, an excitatory ion channel on primary sensory neurons of the pain pathway. Here we show that allicin and DADS excite an allyl isothiocyanate-sensitive subpopulation of sensory neurons and induce vasodilation by activating capsaicin-sensitive perivascular sensory nerve endings. Moreover, allicin and DADS activate the cloned TRPA1 channel when expressed in heterologous systems. These and other results suggest that garlic excites sensory neurons primarily through activation of TRPA1. Thus different plant genera, including Allium and Brassica, have developed evolutionary convergent strategies that target TRPA1 channels on sensory nerve endings to achieve chemical deterrence.
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| 2. |
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| 3. |
- Streng, T., et al.
(author)
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Distribution and Function of the Hydrogen Sulfide-Sensitive TRPA1 Ion Channel in Rat Urinary Bladder
- 2008
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In: European Urology. - : Elsevier BV. - 0302-2838 .- 1873-7560. ; 53:2, s. 391-400
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Journal article (peer-reviewed)abstract
- Objectives: To investigate the distribution of the transient receptor potential (TRP) A1 ion channel in the rat urinary bladder, and to study the effects of hydrogen sulfide (H2S) and known TRPA1 activators on micturition in conscious rats and on heterologously expressed ion channels. Methods: The expression of TRPA1 in urinary bladder was studied with fluorescence immunohistochemistry and real-time PCR in female Sprague-Dawley rats. Cystometric investigations were performed in conscious animals subjected to intravesical administration of sodium hydrogen sulfide (NaHS, donor of H2S), allyl isothiocyanate (AI), and cinnamaldehyde (CA). Fluorometric calcium imaging was used to study the effect of NaHS on human and mouse TRPA1 expressed in CHO cells. Results: TRPA1 immunoreactivity was found on unmyelinated nerve fibres within the urothelium, suburothelial space, and muscle layer as well as around blood vessels throughout the bladder. All TRPA1 immunoreactive nerves fibres also expressed TRPV1 immunoreactivity and vice versa. TRPA1 was also detected in urothelial cells at both transcriptional and protein levels. AI increased micturition frequency and reduced voiding volume. CA and NaHS produced similar changes in urodynamic parameters after disruption of the urothelial barrier with protamine sulfate. NaHS also induced calcium responses in TRPA1-expressing CHO cells, but not in untransfected cells. Conclusions: The expression of TRPA1 on C-fibre bladder afferents and urothelial cells together with the finding that intravesical TRPA1 activators initiate detrusor overactivity indicate that TRPA1 may have a role in sensory transduction in this organ. The study also highlights H2S as a TRPA1 activator potentially involved in inflammatory bladder disease. © 2007.
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| 4. |
- Andersson, David A., et al.
(author)
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Effects of inhibitors of small- and intermediate-conductance calcium-activated potassium channels, inwardly-rectifying potassium channels and Na+/K+ ATPase on EDHF relaxations in the rat hepatic artery
- 2000
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In: British Journal of Pharmacology. - : Wiley. - 0007-1188. ; 129:7, s. 1490-1496
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Journal article (peer-reviewed)abstract
- 1. In the rat hepatic artery, the SK(Ca) inhibitors UCL 1684 (300 nM) completely blocked, and scyllatoxin (1 μM) and d-tubocurarine (100 μM) partially inhibited EDHF relaxations when each of them was combined with charybdotoxin (300 nM). 2. The IK(Ca) inhibitors clotrimazole (3 μM) and 2-chlorophenyl-bisphenyl-methanol (3 μM) strongly depressed EDHF relaxations when each of them was combined with apamin (300 nM). The cytochrome P450 mono-oxygenase inhibitor ketoconazole (10 μM) had no effect in the presence of apamin. 3. Ciclazindol (10 μM), which abolishes EDHF relaxations in the presence of apamin, almost completely prevented the calcium ionophore (A23187) stimulated 86Rb+ influx via the Gardos channel (IK(Ca)) in human erythrocytes. 4. The Na(+/)K+ ATPase inhibitor ouabain (500 μM) and the K(IR) blocker Ba2+ (30 μM) neither alone nor in combination inhibited EDHF relaxations. Ba2+ was also without effect in the presence of either apamin or charybdotoxin. 5. In contrast to EDHF, an increase in extracellular [K+] from 4.6 mM to 9.6, 14.6 and 19.6 mM inconsistently relaxed arteries. In K+-free physiological salt solution, re-admission of K+ always caused complete and sustained relaxations which were abolished by ouabain but unaffected by Ba2+. 6. The present study provides pharmacological evidence for the involvement of SK(Ca) and IK(Ca) in the action of EDHF in the rat hepatic artery. Our results are not consistent with the idea that EDHF is K+ activating Na+/K+ ATPase and K(IR) in this blood vessel.
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| 5. |
- Claeson, Per, et al.
(author)
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Calcium Antagonistic Properties of the Sesquiterpene T‐Cadinol : A Comparison with Nimodipine in the Isolated Rat Aorta
- 1991
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In: Pharmacology and Toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 69:3, s. 173-177
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Journal article (peer-reviewed)abstract
- Abstract: (+)‐T‐Cadinol is a sesquiterpene with smooth muscle relaxing properties. In the isolated rat aorta, T‐cadinol relaxed contractions induced by 60 mM K+ in a concentration‐dependent fashion. The dihydropyridine calcium antagonist nimodipine was approximately 4,000 times more potent than T‐cadinol. While both drugs nearly abolished the K+‐induced contractions, they only partially relaxed contractions induced by phenylephrine. The relaxation induced by T‐cadinol and nimodipine in K+‐contracted aortic rings, was completely reversed by the calcium channel activator Bay K8644. In aortic preparations partially depolarized by 20 mM K+, Bay K8644 induced a concentration‐dependent contraction. Nimodipine shifted the Bay K8644 concentration‐response curve to the right in a parallel manner, consistent with a competitive mode of inhibition. T‐cadinol at concentrations less than 10−3.5 M also produced a right‐ward shift of the Bay K8644 concentration‐response curve with a maintained maximum response. However, the highest T‐cadinol concentration used (10−3.5 M) significantly reduced the maximum response. In conclusion, although T‐cadinol and nimodipine display marked structural differences, their pharmacological profiles of action have several features in common, suggesting that T‐cadinol is a calcium antagonist, possibly interacting with the dihydropyridine binding sites on the calcium channels. 1991 Nordic Pharmacological Society
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| 6. |
- Högestätt, Edward D., et al.
(author)
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Involvement of sensory nerves in vasodilator responses to acetylcholine and potassium ions in rat hepatic artery
- 2000
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In: British Journal of Pharmacology. - : Wiley. - 0007-1188. ; 130:1, s. 27-32
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Journal article (peer-reviewed)abstract
- In the presence of ouabain (1 mM), acetylcholine and KCl (5 mM) evoked endothelium-independent relaxations in rat hepatic arteries. Treatment with capsaicin (10 μM), scopolamine (1 μM) or CGRP8-37 (3 μM) prevented these relaxations. Acetylcholine-induced relaxations in intact arterial segments in the presence of indomethacin (10 μM) and N(G)-nitro-L-arginine (0.3 mM) were only partially inhibited by ouabain plus BaCl2 (30 μM). However, ouabain plus BaCl2 almost abolished such relaxations in capsaicin-pre-treated preparations. In arteries without endothelium, the neurosecretagogue α-latrotoxin (1 nM) induced complete relaxations, which were abolished by CGRP8-37 or pre-treatment with capsaicin. α-Latrotoxin also induced a smooth muscle hyperpolarization (12 ± 2 mV), which was abolished by CGRP8-37. The ability of ouabain to disclose a CGRP-mediated neurogenic relaxation must be considered when this agent is used as a pharmacological tool. The results further suggest that CGRP is a nerve-derived hyperpolarizing factor in the rat hepatic artery.
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| 7. |
- Mirrasekhian, Elahe, 1978-, et al.
(author)
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The antipyretic effect of paracetamol occurs independent of transient receptor potential ankyrin 1–mediated hypothermia and is associated with prostaglandin inhibition in the brain
- 2018
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In: FASEB Journal. - : Federation of American Societies for Experimental Biology. - 0892-6638 .- 1530-6860. ; 32:10, s. 5751-5759
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Journal article (peer-reviewed)abstract
- The mode of action of paracetamol (acetaminophen), which is widely used for treating pain and fever, has remained obscure, but may involve several distinct mechanisms, including cyclooxygenase inhibition and transient receptor potential ankyrin 1 (TRPA1) channel activation, the latter being recently associated with paracetamol’s propensity to elicit hypothermia at higher doses. Here, we examined whether the antipyretic effect of paracetamol was due to TRPA1 activation or cyclooxygenase inhibition. Treatment of wild-type and TRPA1 knockout mice rendered febrile by immune challenge with LPS with a dose of paracetamol that did not produce hypothermia (150 mg/kg) but is known to be analgetic, abolished fever in both genotypes. Paracetamol completely suppressed the LPS-induced elevation of prostaglandin E2 in the brain and also reduced the levels of several other prostanoids. The hypothermia induced by paracetamol was abolished in mice treated with the electrophile-scavenger N-acetyl cysteine. We conclude that paracetamol’s antipyretic effect in mice is dependent on inhibition of cyclooxygenase activity, including the formation of pyrogenic prostaglandin E2, whereas paracetamol-induced hypothermia likely is mediated by the activation of TRPA1 by electrophilic metabolites of paracetamol, similar to its analgesic effect in some experimental paradigms.
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| 8. |
- Moparthi, Lavanya, et al.
(author)
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Human TRPA1 is a heat sensor displaying intrinsic U-shaped thermosensitivity
- 2016
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
-
Journal article (peer-reviewed)abstract
- Thermosensitive Transient Receptor Potential (TRP) channels are believed to respond to either cold or heat. In the case of TRP subtype A1 (TRPA1), there seems to be a species-dependent divergence in temperature sensation as non-mammalian TRPA1 is heat-sensitive whereas mammalian TRPA1 is sensitive to cold. It has been speculated but never experimentally proven that TRPA1 and other temperature-sensitive ion channels have the inherent capability of responding to both cold and heat. Here we show that redox modification and ligands affect human TRPA1 (hTRPA1) cold and heat sensing properties in lipid bilayer and whole-cell patch-clamp recordings as well as heat-evoked TRPA1-dependent calcitonin gene-related peptide (CGRP) release from mouse trachea. Studies of purified hTRPA1 intrinsic tryptophan fluorescence, in the absence of lipid bilayer, consolidate hTRPA1 as an intrinsic bidirectional thermosensor that is modified by the redox state and ligands. Thus, the heat sensing property of TRPA1 is conserved in mammalians, in which TRPA1 may contribute to sensing warmth and uncomfortable heat in addition to noxious cold.
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| 9. |
- Nilsson, Johan L.Å., et al.
(author)
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N,N'-Bis(2-mercaptoethyl)isophthalamide Binds Electrophilic Paracetamol Metabolites and Prevents Paracetamol-Induced Liver Toxicity
- 2018
-
In: Basic and Clinical Pharmacology and Toxicology. - : Wiley. - 1742-7835. ; 123:5, s. 589-593
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Journal article (peer-reviewed)abstract
- Paracetamol overdosing may cause liver injury including fulminant liver failure due to generation of the toxic metabolites, N-acetyl-p-benzoquinone imine (NAPQI) and p-benzoquinone (p-BQ). Herein, the chelating agent, N,N'-Bis(2-mercaptoethyl)isophthalamide (NBMI), was examined for its potential ability to entrap NAPQI and p-BQ and to prevent paracetamol-induced liver injury. Both NBMI and the conventional paracetamol antidote N-acetylcysteine (NAC) were investigated with regard to their abilities to scavenge the NAPQI and p-BQ in a Transient Receptor Potential Ankyrin 1-dependent screening assay. Stoichiometric evaluations indicated that NBMI was able to entrap these metabolites more efficiently than NAC. Furthermore, oral administration of either NBMI (680 mg/kg) or NAC (680 mg/kg) prevented the development of the characteristic liver necrosis and elevation of serum alanine aminotransferase in a mouse model for paracetamol-induced liver injury. In summary, these results show that NBMI is able to entrap the toxic metabolites NAPQI and p-BQ and to prevent paracetamol-induced liver injury in mice.
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| 10. |
- Survery, Sabeen, et al.
(author)
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The N-terminal Ankyrin Repeat domain is not required for electrophile and heat activation of the purified mosquito TRPA1 receptor
- 2016
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In: Journal of Biological Chemistry. - 0021-9258. ; 291:52, s. 26899-26912
-
Journal article (peer-reviewed)abstract
- Temperature sensors are crucial for animals to optimize living conditions. The temperature response of the ion channel transient receptor potential A1 (TRPA1) is intriguing; some orthologs have been reported to be activated by cold and others by heat, but the molecular mechanisms responsible for its activation remain elusive. Single-channel electrophysiological recordings of heterologously expressed and purified Anopheles gambiae TRPA1 (AgTRPA1), with and without the N-terminal ankyrin repeat domain, demonstrate that both proteins are functional because they responded to the electrophilic compounds allyl isothiocyanate and cinnamaldehyde as well as heat. The proteins' similar intrinsic fluorescence properties and corresponding quenching when activated by allyl isothiocyanate or heat suggest lipid bilayer-independent conformational changes outside the N-terminal domain. The results show that Ag- TRPA1 is an inherent thermo- and chemoreceptor, and analogous to what has been reported for the human TRPA1 ortholog, the N-terminal domain may tune the response but is not required for the activation by these stimuli.
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| 11. |
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| 12. |
- Zygmunt, Peter M., et al.
(author)
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Interactions between endothelium-derived relaxing factors in the rat hepatic artery : Focus on regulation of EDHF
- 1998
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In: British Journal of Pharmacology. - : Wiley. - 0007-1188. ; 124:5, s. 992-1000
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Journal article (peer-reviewed)abstract
- 1. In rat isolated hepatic arteries contracted with phenylephrine, acetylcholine and the calcium ionophore A23187 each elicit endothelium-dependent relaxations, which involve both nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF). However, the contribution of prostanoids to these responses, and the potential interaction between EDHF and other endothelium-derived relaxing factors have not been examined. 2. In the presence of the NO synthase inhibitor N(G)-nitro-L-arginine (L-NOARG, 0.3 mM) and a mixture of charybdotoxin (0.3 μM) and apamin (0.3 μM), inhibitors of the target potassium (K) channel(s) for EDHF, acetylcholine and A23187 each induced a concentration-dependent and almost complete relaxation, which was abolished in the additional presence of indomethacin (10 μM). Thus, in addition to EDHF and NO, a relaxing factor(s) generated by cyclo-oxygenase (COX) contributes to endothelium-dependent relaxation in the rat hepatic artery. 3. The resting membrane potentials of endothelium-intact and endothelium-denuded vascular segments were -57 mV and -52 mV, respectively (P > 0.05). In intact arteries, the resting membrane potential was not affected by L-NOARG plus indomethacin, but reduced to -47 mV in the presence of charybdotoxin plus apamin. Acetylcholine and A23187 (10 μM each) elicited a hyperpolarization of 13 mV and 15 mV, respectively. The hyperpolarization induced by these agents was not affected by L-NOARG plus indomethacin (12 mV and 14 mV, respectively), but reduced in the presence of charybdotoxin plus apamin (7 mV and 10 mV, respectively), and abolished in the combined presence of charybdotoxin, apamin and indomethacin. 4. The NO donor 3-morpholino-sydnonimine (SIN-1) induced a concentration-dependent relaxation, which was unaffected by charybdotoxin plus apamin, but abolished by the selective soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ, 10 μM). SIN-1 (10 μM) did not alter the resting membrane potential in endothelium-denuded vascular segments. 5. The COX-dependent relaxation induced by acetylcholine was abolished following exposure to 30 mM KCl, but unaffected by glibenclamide (10 μM). The prostacyclin analogue iloprost induced a concentration-dependent relaxation, which was also abolished in 30 mM KCl and unaffected by the combined treatment with glibenclamide, charybdotoxin and apamin. Iloprost (10 μM) induced a glibenclamide-resistant hyperpolarization (8 mV with and 9 mV without glibenclamide) in endothelium-denuded vascular segments. 6. Exposure to SIN-1 or iloprost did not affect the EDHF-mediated relaxation induced by acetylcholine (i.e. in the presence of L-NOARG and indomethacin). Replacement of L-NOARG with the NO scavenger oxyhaemoglobin (10 μM) or the soluble guanylate cyclase inhibitor ODQ (10 μM) or methylene blue (10 μM), which all significantly inhibited responses to endothelium-derived NO, did not affect the acetylcholine-induced relaxation in the presence of indomethacin, indicating that endogenous NO also does not suppress EDHF-mediated responses. 7. These results show that, in addition to EDHF and NO, an endothelium-derived hyperpolarizing factor(s) generated by COX contributes significantly to endothelium-dependent relaxation in the rat heptic artery. Neither this factor nor NO seems to regulate EDHF-mediated responses. Thus, EDHF does not serve simply as a 'back-up' system for NO and prostacyclin in this artery. However, whether EDHF modulates the NO and COX pathways remains to be determined.
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| 13. |
- Zygmunt, Peter M., et al.
(author)
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Involvement of voltage-dependent potassium channels in the EDHF-mediated relaxation of rat hepatic artery
- 1997
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In: British Journal of Pharmacology. - : Wiley. - 0007-1188. ; 121:1, s. 141-149
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Journal article (peer-reviewed)abstract
- 1. In the rat hepatic artery, the acetylcholine-induced relaxation mediated by endothelium-derived hyperpolarizing factor (EDHF) is abolished by a combination of apamin and charybdotoxin, inhibitors of small (SK(Ca)) and large (BK(Ca)) conductance calcium-sensitive potassium (K)-channels, respectively, but not by each toxin alone. The selective BK(Ca) inhibitor iberiotoxin cannot replace charybdotoxin in this combination. Since delayed rectifier K-channels (K(V)) represent another target for charybdotoxin, we explored the possible involvement of K(V) in EDHF-mediated relaxation in this artery. 2. The K(V) inhibitors, agitoxin-2 (0.3 μM), kaliotoxin (0.3 μM), β-dendrotoxin (0.3 μM), dofetilide (1 μM) and terikalant (10 μM), each in combination with apamin (0.3 μM) had no effect on the EDHF-mediated relaxation induced by acetylcholine in the presence of N(ω)-nitro-L-arginine (0.3 mM) and indomethacin (10 μM), inhibitors of nitric oxide (NO) synthase and cyclo-oxygenase, respectively (n = 2-3). Although the K(V) inhibitor margatoxin (0.3 μM) was also without effect (n = 5), the combination of margatoxin and apamin produced a small inhibition of the response (pEC50 and E(max) values were 7.5 ± 0.0 and 95 ± 1% in the absence and 7.0 ± 0.1 and 81 ± 6% in the presence of margatoxin plus apamin, respectively; n = 6; P < 0.05). 3. Ciclazindol (10 μM) partially inhibited the EDHF-mediated relaxation by shifting the acetylcholine-concentration-response curve 12 fold to the right (n =.6; P < 0.05) and abolished the response when combined with apamin (0.3 μM; n = 6). This combination did not inhibit acetylcholine-induced relaxations mediated by endothelium-derived NO (n = 5). 4. A 4-aminopyridine-sensitive delayed rectifier current (I(K(V))) was identified in freshly-isolated single smooth muscle cells from rat hepatic artery. None of the cells displayed a rapidly-activating and -inactivating A-type current. Neither charybdotoxin (0.3 μM; n = 3) nor ciclazindol (10 μM; n = 5), alone or in combination with apamin (0.3 μM; n = 4-5), had an effect on I(K(V)). A tenfold higher concentration of ciclazindol (0.1 mM, n = 4) markedly inhibited I(K(V)), but this effect was not increased in the additional presence of apamin (0.3 μM; n = 2). 5. By use of membranes prepared from rat brain cortex, [125I]-charybdotoxin binding was consistent with an interaction at a single site with a K(D) of approximately 25 pM. [125I]-charybdotoxin binding was unaffected by iberiotoxin (0.1 μM, n = 6), but was increased by apamin in a concentration-dependent manner (E(max) 43 ± 10%, P < 0.05 and pEC50 7.1 ± 0.2; n = 7-8). Agitoxin-2 (10 nM) displaced [125I]-charybdotoxin binding by 91 ± 3% (n = 6) and prevented the effect of apamin (1 μM; n = 6). 6. It is concluded that the EDHF-mediated relaxation in the rat hepatic artery is not mediated by the opening of either K(V) or BK(Ca). Instead, the target K-channels for EDHF seem to be structurally related to both K(V) and BK(Ca). The possibility that a subtype of SK(Ca) may be the target for EDHF is discussed.
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| 14. |
- Zygmunt, Peter M., et al.
(author)
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The anandamide transport inhibitor AM404 activates vanilloid receptors
- 2000
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In: European Journal of Pharmacology. - 0014-2999. ; 396:1, s. 39-42
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Journal article (peer-reviewed)abstract
- The possibility that the anandamide transport inhibitor N-(4-hydroxyphenyl)-5,8,11,14-eicosatetraenamide (AM404), structurally similar to the vanilloid receptor agonists anandamide and capsaicin, may also activate vanilloid receptors and cause vasodilation was examined. AM404 evoked concentration-dependent relaxations in segments of rat isolated hepatic artery contracted with phenylephrine. Relaxations were abolished in preparations pre-treated with capsaicin. The calcitonin-gene related peptide (CGRP) receptor antagonist CGRP-(8-37) also abolished relaxations. The vanilloid receptor antagonist capsazepine inhibited vasodilation by AM404 and blocked AM404-induced currents in patch-clamp experiments on Xenopus oocytes expressing the vanilloid subtype 1 receptor (VR1). In conclusion, AM404 activates native and cloned vanilloid receptors. Copyright (C) 2000 Elsevier Science B.V.
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| 15. |
- Zygmunt, Peter M., et al.
(author)
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Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide
- 1999
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 400:6743, s. 452-457
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Journal article (peer-reviewed)abstract
- The endogenous cannabinoid receptor agonist anandamide is a powerful vasodilator of isolated vascular preparations, but its mechanism of action is unclear. Here we show that the vasodilator response to anandamide in isolated arteries is capsaicin-sensitive and accompanied by release of calcitonin- gene-related peptide (CGRP). The selective CGRP-receptor antagonist 8-37 CGRP (ref. 5), but not the cannabinoid CB1 receptor blocker SR141716A (ref. 7), inhibited the vasodilator effect of anandamide. Other endogenous. (2- arachidonylglycerol, palmitylethanolamide) and synthetic (HU 210, WIN 55,212- 2, CP 55,940) CB1 and CB2 receptor agonists could not mimic the action of anandamide. The selective 'vanilloid receptor' antagonist capsazepine inhibited anandamide-induced vasodilation and release of CGRP. In patch-clamp experiments on cells expressing the cloned vanilloid receptor (VR1), anandamide induced a capsazepine-sensitive current in whole cells and isolated membrane patches. Our results indicate that anandamide induces vasodilation by activating vanilloid receptors on perivascular sensory nerves and causing release of CGRP. The vanilloid receptor may thus be another molecular target for endogenous anandamide, besides cannabinoid receptors, in the nervous and cardiovascular systems.
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