Trans-4-methoxy-β-nitrostyrene relaxes rat thoracic aorta through a sGC-dependent pathway
| Autor: | Pedro Jorge Caldas Magalhães, Loeste Arruda-Barbosa, Taylena Maria Teófilo, Joyce K. L. Vale, Rosivaldo S. Borges, Gloria Pinto Duarte, Francisco das Chagas Vasconcelos Souza-Neto, Saad Lahlou |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Vascular smooth muscle Potassium Channels Stereochemistry Intracellular Space Stimulation Aorta Thoracic Pharmacology Potassium Chloride Styrenes 03 medical and health sciences chemistry.chemical_compound Phenylephrine 0302 clinical medicine medicine.artery medicine Extracellular Thoracic aorta Animals Calcium Signaling Rats Wistar Protein kinase C Tetraethylammonium Chemistry Activator (genetics) Rats Vasodilation 030104 developmental biology Solubility Guanylate Cyclase Vasoconstriction cardiovascular system Calcium Channels Endothelium Vascular 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | European journal of pharmacology. 807 |
| ISSN: | 1879-0712 |
| Popis: | 1-Nitro-2-phenylethene (NPe) induces a more potent vasorelaxant effect in rat aorta than its structural analog 1-nitro-2-phenylethane, but mediated through a different mechanism, independent of soluble guanylate cyclase (sGC) stimulation. We hypothesized that introducing an electron donor into the aromatic moiety might stabilize NPe, enhancing its potency and/or interaction with sGC. Therefore, trans-4-methoxy-β-nitrostyrene (T4MN) was synthesized, and mechanisms underlying its vasorelaxant effects were studied in rat aortic ring preparations. In endothelium-intact preparations, T4MN fully relaxed contractions induced by phenylephrine (PHE) with a potency similar to that of its parent drug, NPe. This vasorelaxant effect that was unchanged by endothelium removal, pretreatment with L-NAME, indomethacin, or MDL-12,330 A, but was significantly reduced by tetraethylammonium, 4-aminopyridine, methyl blue, or ODQ. Under Ca 2+ -free conditions, T4MN did not alter contractions evoked by caffeine, but significantly reduced, in an ODQ-preventable manner, those induced by either PHE or extracellular Ca 2+ restoration following depletion of intracellular Ca 2+ stores in thapsigargin-treated aortic preparations. Under the same conditions, T4MN also reduced contractions induced by protein kinase C activator phorbol-12,13-dibutyrate with a potency similar to that evoked by this nitroderivative against PHE-induced contractions. In conclusion, T4MN induces potent vasorelaxation in rat aorta by stimulating the sGC-cGMP pathway through a NO-independent mechanism. Introduction of a methoxy group into the aromatic moiety apparently stabilizes NPe, thereby enhancing its interaction with sGC. |
| Databáze: | OpenAIRE |
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