Comparison of vasorelaxant effect and tolerance profile of a novel isosorbide-5-mononitrate derivative with its stereoisomer and parent drug on rat mesenteric artery
Нема приказа
Аутори
Stepanović-Petrović, RadicaSavić, Vladimir
Tomić, Maja
Tokić-Vujošević, Zorana
Simić, Milena
Stepanović, Jelena M.
Jokanović, Milan
Micov, Ana
Чланак у часопису (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт
Background/Aims: 5-Ketoximeisosorbide-2-mononitrate (50-IS-2-MN) was synthesized and its pharmacological and toxicological characteristics were examined and compared with its parent drug, isosorbide-5-mononitrate (IS-5-MN, CAS 16051-77-7), and its diastereoisomer 2-ketoximeisosorbide-5-mononitrate. Methods: Vasorelaxation was studied on phenylephrine-precontracted rat superior mesenteric artery rings in organ bath procedure. In some rings, the endothelium was mechanically removed. In vitro tolerance was induced by treating the precontracted rings with maximal concentrations of the parent drug and the ketoximes, and after washing out, the procedure was repeated for two times. Furthermore, rats were treated with a single oral dose (1000 mg/kg) of 50-IS-2-MN and 20-IS-5-MN. Results: After a phenylephrine-induced contraction, 50-IS-2-MN (10(-8)-10(-4) mol/l) caused a concentration-dependent relaxation of the rat superior mesenteric artery that was strongly potentiated after the removal of ...the vascular endothelium. In preparations with or without endothelium, 50-IS-2-MN was a more potent relaxant than either the parent compound or its isomer. The mechanism of the relaxant effect of 50-IS-2-MN involves the activated soluble guanylyl cyclase-cyclic GMP pathway. Hydralazine (10(-5) mol/l), a strong antioxidant, ameliorated tolerance to IS-5-MN, but did not affect the absence of tolerance to either ketoxime. The minimum lethal dose in rat for 50-IS-2-MN and 20-IS-5-MN was greater than 1000 mg/kg. Conclusion: These results suggest that the modification of the configuration at the ester carbon of IS-5-MN contributes to more potent and tolerance-devoid activity on the rat superior mesenteric artery.
Кључне речи:
Endothelium / Hydralazine / 5-Ketoximeisosorbide-2-mononitrate / Nitrate tolerance / Organic nitratesИзвор:
Arzneimittelforschung - Drug Research, 2010, 60, 4, 189-197Издавач:
- ECV-Editio Cantor Verlag Medizin Naturwissenschaften, Aulendorf
Финансирање / пројекти:
- Испитивање механизма дејства, интеракција и токсичних ефеката аналгетика као и вазоактивних супстанци (RS-MESTD-MPN2006-2010-145030)
DOI: 10.1055/s-0031-1296272
ISSN: 0004-4172
PubMed: 20486469
WoS: 000277339600006
Scopus: 2-s2.0-77951701398
Институција/група
PharmacyTY - JOUR AU - Stepanović-Petrović, Radica AU - Savić, Vladimir AU - Tomić, Maja AU - Tokić-Vujošević, Zorana AU - Simić, Milena AU - Stepanović, Jelena M. AU - Jokanović, Milan AU - Micov, Ana PY - 2010 UR - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1337 AB - Background/Aims: 5-Ketoximeisosorbide-2-mononitrate (50-IS-2-MN) was synthesized and its pharmacological and toxicological characteristics were examined and compared with its parent drug, isosorbide-5-mononitrate (IS-5-MN, CAS 16051-77-7), and its diastereoisomer 2-ketoximeisosorbide-5-mononitrate. Methods: Vasorelaxation was studied on phenylephrine-precontracted rat superior mesenteric artery rings in organ bath procedure. In some rings, the endothelium was mechanically removed. In vitro tolerance was induced by treating the precontracted rings with maximal concentrations of the parent drug and the ketoximes, and after washing out, the procedure was repeated for two times. Furthermore, rats were treated with a single oral dose (1000 mg/kg) of 50-IS-2-MN and 20-IS-5-MN. Results: After a phenylephrine-induced contraction, 50-IS-2-MN (10(-8)-10(-4) mol/l) caused a concentration-dependent relaxation of the rat superior mesenteric artery that was strongly potentiated after the removal of the vascular endothelium. In preparations with or without endothelium, 50-IS-2-MN was a more potent relaxant than either the parent compound or its isomer. The mechanism of the relaxant effect of 50-IS-2-MN involves the activated soluble guanylyl cyclase-cyclic GMP pathway. Hydralazine (10(-5) mol/l), a strong antioxidant, ameliorated tolerance to IS-5-MN, but did not affect the absence of tolerance to either ketoxime. The minimum lethal dose in rat for 50-IS-2-MN and 20-IS-5-MN was greater than 1000 mg/kg. Conclusion: These results suggest that the modification of the configuration at the ester carbon of IS-5-MN contributes to more potent and tolerance-devoid activity on the rat superior mesenteric artery. PB - ECV-Editio Cantor Verlag Medizin Naturwissenschaften, Aulendorf T2 - Arzneimittelforschung - Drug Research T1 - Comparison of vasorelaxant effect and tolerance profile of a novel isosorbide-5-mononitrate derivative with its stereoisomer and parent drug on rat mesenteric artery VL - 60 IS - 4 SP - 189 EP - 197 DO - 10.1055/s-0031-1296272 UR - https://hdl.handle.net/21.15107/rcub_farfar_1337 ER -
@article{ author = "Stepanović-Petrović, Radica and Savić, Vladimir and Tomić, Maja and Tokić-Vujošević, Zorana and Simić, Milena and Stepanović, Jelena M. and Jokanović, Milan and Micov, Ana", year = "2010", abstract = "Background/Aims: 5-Ketoximeisosorbide-2-mononitrate (50-IS-2-MN) was synthesized and its pharmacological and toxicological characteristics were examined and compared with its parent drug, isosorbide-5-mononitrate (IS-5-MN, CAS 16051-77-7), and its diastereoisomer 2-ketoximeisosorbide-5-mononitrate. Methods: Vasorelaxation was studied on phenylephrine-precontracted rat superior mesenteric artery rings in organ bath procedure. In some rings, the endothelium was mechanically removed. In vitro tolerance was induced by treating the precontracted rings with maximal concentrations of the parent drug and the ketoximes, and after washing out, the procedure was repeated for two times. Furthermore, rats were treated with a single oral dose (1000 mg/kg) of 50-IS-2-MN and 20-IS-5-MN. Results: After a phenylephrine-induced contraction, 50-IS-2-MN (10(-8)-10(-4) mol/l) caused a concentration-dependent relaxation of the rat superior mesenteric artery that was strongly potentiated after the removal of the vascular endothelium. In preparations with or without endothelium, 50-IS-2-MN was a more potent relaxant than either the parent compound or its isomer. The mechanism of the relaxant effect of 50-IS-2-MN involves the activated soluble guanylyl cyclase-cyclic GMP pathway. Hydralazine (10(-5) mol/l), a strong antioxidant, ameliorated tolerance to IS-5-MN, but did not affect the absence of tolerance to either ketoxime. The minimum lethal dose in rat for 50-IS-2-MN and 20-IS-5-MN was greater than 1000 mg/kg. Conclusion: These results suggest that the modification of the configuration at the ester carbon of IS-5-MN contributes to more potent and tolerance-devoid activity on the rat superior mesenteric artery.", publisher = "ECV-Editio Cantor Verlag Medizin Naturwissenschaften, Aulendorf", journal = "Arzneimittelforschung - Drug Research", title = "Comparison of vasorelaxant effect and tolerance profile of a novel isosorbide-5-mononitrate derivative with its stereoisomer and parent drug on rat mesenteric artery", volume = "60", number = "4", pages = "189-197", doi = "10.1055/s-0031-1296272", url = "https://hdl.handle.net/21.15107/rcub_farfar_1337" }
Stepanović-Petrović, R., Savić, V., Tomić, M., Tokić-Vujošević, Z., Simić, M., Stepanović, J. M., Jokanović, M.,& Micov, A.. (2010). Comparison of vasorelaxant effect and tolerance profile of a novel isosorbide-5-mononitrate derivative with its stereoisomer and parent drug on rat mesenteric artery. in Arzneimittelforschung - Drug Research ECV-Editio Cantor Verlag Medizin Naturwissenschaften, Aulendorf., 60(4), 189-197. https://doi.org/10.1055/s-0031-1296272 https://hdl.handle.net/21.15107/rcub_farfar_1337
Stepanović-Petrović R, Savić V, Tomić M, Tokić-Vujošević Z, Simić M, Stepanović JM, Jokanović M, Micov A. Comparison of vasorelaxant effect and tolerance profile of a novel isosorbide-5-mononitrate derivative with its stereoisomer and parent drug on rat mesenteric artery. in Arzneimittelforschung - Drug Research. 2010;60(4):189-197. doi:10.1055/s-0031-1296272 https://hdl.handle.net/21.15107/rcub_farfar_1337 .
Stepanović-Petrović, Radica, Savić, Vladimir, Tomić, Maja, Tokić-Vujošević, Zorana, Simić, Milena, Stepanović, Jelena M., Jokanović, Milan, Micov, Ana, "Comparison of vasorelaxant effect and tolerance profile of a novel isosorbide-5-mononitrate derivative with its stereoisomer and parent drug on rat mesenteric artery" in Arzneimittelforschung - Drug Research, 60, no. 4 (2010):189-197, https://doi.org/10.1055/s-0031-1296272 ., https://hdl.handle.net/21.15107/rcub_farfar_1337 .