FarFaR - Pharmacy Repository
University of Belgrade, Faculty of Pharmacy
    • English
    • Српски
    • Српски (Serbia)
  • English 
    • English
    • Serbian (Cyrillic)
    • Serbian (Latin)
  • Login
View Item 
  •   FarFaR
  • Pharmacy
  • Radovi istraživača / Researchers’ publications
  • View Item
  •   FarFaR
  • Pharmacy
  • Radovi istraživača / Researchers’ publications
  • View Item
JavaScript is disabled for your browser. Some features of this site may not work without it.

Comparison of vasorelaxant effect and tolerance profile of a novel isosorbide-5-mononitrate derivative with its stereoisomer and parent drug on rat mesenteric artery

No Thumbnail
Authors
Stepanović-Petrović, Radica
Savić, Vladimir
Tomić, Maja
Tokić-Vujošević, Zorana
Simić, Milena
Stepanović, Jelena M.
Jokanović, Milan
Micov, Ana
Article (Published version)
Metadata
Show full item record
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.

Keywords:
Endothelium / Hydralazine / 5-Ketoximeisosorbide-2-mononitrate / Nitrate tolerance / Organic nitrates
Source:
Arzneimittelforschung - Drug Research, 2010, 60, 4, 189-197
Publisher:
  • ECV-Editio Cantor Verlag Medizin Naturwissenschaften, Aulendorf
Funding / projects:
  • Ispitivanje mehanizma dejstva, interakcija i toksičnih efekata analgetika kao i vazoaktivnih supstanci (RS-145030)

DOI: 10.1055/s-0031-1296272

ISSN: 0004-4172

PubMed: 20486469

WoS: 000277339600006

Scopus: 2-s2.0-77951701398
[ Google Scholar ]
Handle
https://hdl.handle.net/21.15107/rcub_farfar_1337
URI
https://farfar.pharmacy.bg.ac.rs/handle/123456789/1337
Collections
  • Radovi istraživača / Researchers’ publications
Institution/Community
Pharmacy
TY  - 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 .

DSpace software copyright © 2002-2015  DuraSpace
About FarFaR - Pharmacy Repository | Send Feedback

OpenAIRERCUB
 

 

All of DSpaceCommunitiesAuthorsTitlesSubjectsThis institutionAuthorsTitlesSubjects

Statistics

View Usage Statistics

DSpace software copyright © 2002-2015  DuraSpace
About FarFaR - Pharmacy Repository | Send Feedback

OpenAIRERCUB