The bitter taste receptor (TAS2R) agonist denatonium promotes a strong relaxation of rat corpus cavernosum
Copyright © 2023 Elsevier Inc. All rights reserved..
Bitter taste receptors (TAS2R) are found in numerous extra-oral tissues, including smooth muscle (SM) cells in both vascular and visceral tissues. Upon activation, TAS2R stimulate the relaxation of the SM. Nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling pathway is involved in penile erection, and type 5 phosphodiesterase (PDE5) inhibitors, a cGMP-specific hydrolase are used as first-line treatments for erectile dysfunction (ED). Nevertheless, PDE5 inhibitors are ineffective in a considerable number of patients, prompting research into alternative pharmacological targets for ED. Since TAS2R agonists regulate SM contractility, this study investigates the role of TAS2Rs in rat corpus cavernosum (CC). We performed immunohistochemistry to detect TAS2R10, isometric force recordings for TAS2R agonists denatonium and chloroquine, the slow-release H2S donor GYY 4137, the NO donor SNAP, the β-adrenoceptor agonist isoproterenol and electrical field stimulation (EFS), as well as measurement of endogenous hydrogen sulfide (H2S) production. The immunofluorescence staining indicated that TAS2R10 was broadly expressed in the CC SM and to some extent in the nerve fibers. Denatonium, chloroquine, SNAP, and isoproterenol cause potent dose-dependent SM relaxations. H2S production was decreased by NO and H2S synthase inhibitors, while it was enhanced by denatonium. In addition, denatonium increased the relaxations induced by GYY 4137 and SNAP but failed to modify EFS- and isoproterenol-induced responses. These results suggest neuronal and SM TAS2R10 expression in the rat CC, where denatonium induces a strong SM relaxation per se and promotes the H2S- and NO-mediated inhibitory gaseous neurotransmission. Thus, TAS2R10 might represent a valuable therapeutic target in ED.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:215 |
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| Enthalten in: |
Biochemical pharmacology - 215(2023) vom: 15. Sept., Seite 115754 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Navarro-Dorado, Jorge [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 06.09.2023 Date Revised 18.09.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.bcp.2023.115754 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 4 | |a The bitter taste receptor (TAS2R) agonist denatonium promotes a strong relaxation of rat corpus cavernosum |
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| 520 | |a Copyright © 2023 Elsevier Inc. All rights reserved. | ||
| 520 | |a Bitter taste receptors (TAS2R) are found in numerous extra-oral tissues, including smooth muscle (SM) cells in both vascular and visceral tissues. Upon activation, TAS2R stimulate the relaxation of the SM. Nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling pathway is involved in penile erection, and type 5 phosphodiesterase (PDE5) inhibitors, a cGMP-specific hydrolase are used as first-line treatments for erectile dysfunction (ED). Nevertheless, PDE5 inhibitors are ineffective in a considerable number of patients, prompting research into alternative pharmacological targets for ED. Since TAS2R agonists regulate SM contractility, this study investigates the role of TAS2Rs in rat corpus cavernosum (CC). We performed immunohistochemistry to detect TAS2R10, isometric force recordings for TAS2R agonists denatonium and chloroquine, the slow-release H2S donor GYY 4137, the NO donor SNAP, the β-adrenoceptor agonist isoproterenol and electrical field stimulation (EFS), as well as measurement of endogenous hydrogen sulfide (H2S) production. The immunofluorescence staining indicated that TAS2R10 was broadly expressed in the CC SM and to some extent in the nerve fibers. Denatonium, chloroquine, SNAP, and isoproterenol cause potent dose-dependent SM relaxations. H2S production was decreased by NO and H2S synthase inhibitors, while it was enhanced by denatonium. In addition, denatonium increased the relaxations induced by GYY 4137 and SNAP but failed to modify EFS- and isoproterenol-induced responses. These results suggest neuronal and SM TAS2R10 expression in the rat CC, where denatonium induces a strong SM relaxation per se and promotes the H2S- and NO-mediated inhibitory gaseous neurotransmission. Thus, TAS2R10 might represent a valuable therapeutic target in ED | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Bitter taste receptors | |
| 650 | 4 | |a Denatonium | |
| 650 | 4 | |a Rat corpus cavernosum | |
| 650 | 4 | |a Smooth muscle relaxation | |
| 650 | 4 | |a TAS2R agonists | |
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| 650 | 7 | |a denatonium |2 NLM | |
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| 650 | 7 | |a Isoproterenol |2 NLM | |
| 650 | 7 | |a L628TT009W |2 NLM | |
| 650 | 7 | |a Chloroquine |2 NLM | |
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| 650 | 7 | |a Cyclic GMP |2 NLM | |
| 650 | 7 | |a H2D2X058MU |2 NLM | |
| 700 | 1 | |a Climent, Belén |e verfasserin |4 aut | |
| 700 | 1 | |a López-Oliva, María Elvira |e verfasserin |4 aut | |
| 700 | 1 | |a Pilar Martínez, María |e verfasserin |4 aut | |
| 700 | 1 | |a Hernández-Martín, Marina |e verfasserin |4 aut | |
| 700 | 1 | |a Agis-Torres, Ángel |e verfasserin |4 aut | |
| 700 | 1 | |a Recio, Paz |e verfasserin |4 aut | |
| 700 | 1 | |a Victoria Barahona, María |e verfasserin |4 aut | |
| 700 | 1 | |a Benedito, Sara |e verfasserin |4 aut | |
| 700 | 1 | |a Fernandes, Vítor S |e verfasserin |4 aut | |
| 700 | 1 | |a Hernández, Medardo |e verfasserin |4 aut | |
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