Comparison of the relaxant effects of a new oxime-nitrate derived from isosorbide-5-mononitrate and the parent drug
Abstract
The transformation of isosorbide-5-mononitrate (CAS 16051-77-7, IS-5-MN) to the corresponding keto derivative and its ketoxime (oxime-nitrate derivative of isosorbide) is described. The effects of IS-5-MN and the new oxime-nitrate (ON) on the endothelial and smooth muscle cells of isolated rings of the rat superior mesenteric artery were examined. After contraction induced by phenylephrine, IS-5-MN (10(-8)-10(-4) mol/1) caused a concentration-dependent relaxation. Removal of the vascular endothelium strongly potentiated this effect. On the other hand, the new ON (10(-8)-10(-4) mol/1) was a more potent relaxant than the parent drug, but its effect was not dependent on the vascular endothelium. The inhibitory effect of the artery without endothelium to the new ON was more pronounced than that to IS-5-MN. The mechanism of the relaxant effect of the new compound consisted in the liberation of nitric-oxide (NO) which activated guanylate cyclase (GC), upon which accumulation of cyclic guanos...ine monophosphate (cGMP) occurred, which was the second messenger leading to relaxation. Tolerance to the frequent applications of the new compound was not observed, moreover a slight increase of the effect was detected in comparison with IS-5-MN for which tolerance was observed to a great extent. Clinically, the new ON could be favorable in all types of angina in comparison with the classical IS-5-MN.
Keywords:
CAS 1-6051-77-7 / isosorbide-5-mononitrate / oxime-nitrate / oxime-nitrate derivative / endothelium-dependent relaxation / rat superior mesenteric artery / toleranceSource:
Arzneimittelforschung - Drug Research, 2004, 54, 4, 195-202Publisher:
- Georg Thieme Verlag Kg, Stuttgart
DOI: 10.1055/s-0031-1296959
ISSN: 0004-4172
PubMed: 15146931
WoS: 000221315400001
Scopus: 2-s2.0-1942500196
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PharmacyTY - JOUR AU - Stepanović-Petrović, Radica AU - Tokić-Vujošević, Zorana AU - Milovanović, S AU - Ceković, Z AU - Tomić, Maja PY - 2004 UR - https://farfar.pharmacy.bg.ac.rs/handle/123456789/476 AB - The transformation of isosorbide-5-mononitrate (CAS 16051-77-7, IS-5-MN) to the corresponding keto derivative and its ketoxime (oxime-nitrate derivative of isosorbide) is described. The effects of IS-5-MN and the new oxime-nitrate (ON) on the endothelial and smooth muscle cells of isolated rings of the rat superior mesenteric artery were examined. After contraction induced by phenylephrine, IS-5-MN (10(-8)-10(-4) mol/1) caused a concentration-dependent relaxation. Removal of the vascular endothelium strongly potentiated this effect. On the other hand, the new ON (10(-8)-10(-4) mol/1) was a more potent relaxant than the parent drug, but its effect was not dependent on the vascular endothelium. The inhibitory effect of the artery without endothelium to the new ON was more pronounced than that to IS-5-MN. The mechanism of the relaxant effect of the new compound consisted in the liberation of nitric-oxide (NO) which activated guanylate cyclase (GC), upon which accumulation of cyclic guanosine monophosphate (cGMP) occurred, which was the second messenger leading to relaxation. Tolerance to the frequent applications of the new compound was not observed, moreover a slight increase of the effect was detected in comparison with IS-5-MN for which tolerance was observed to a great extent. Clinically, the new ON could be favorable in all types of angina in comparison with the classical IS-5-MN. PB - Georg Thieme Verlag Kg, Stuttgart T2 - Arzneimittelforschung - Drug Research T1 - Comparison of the relaxant effects of a new oxime-nitrate derived from isosorbide-5-mononitrate and the parent drug VL - 54 IS - 4 SP - 195 EP - 202 DO - 10.1055/s-0031-1296959 UR - https://hdl.handle.net/21.15107/rcub_farfar_476 ER -
@article{ author = "Stepanović-Petrović, Radica and Tokić-Vujošević, Zorana and Milovanović, S and Ceković, Z and Tomić, Maja", year = "2004", abstract = "The transformation of isosorbide-5-mononitrate (CAS 16051-77-7, IS-5-MN) to the corresponding keto derivative and its ketoxime (oxime-nitrate derivative of isosorbide) is described. The effects of IS-5-MN and the new oxime-nitrate (ON) on the endothelial and smooth muscle cells of isolated rings of the rat superior mesenteric artery were examined. After contraction induced by phenylephrine, IS-5-MN (10(-8)-10(-4) mol/1) caused a concentration-dependent relaxation. Removal of the vascular endothelium strongly potentiated this effect. On the other hand, the new ON (10(-8)-10(-4) mol/1) was a more potent relaxant than the parent drug, but its effect was not dependent on the vascular endothelium. The inhibitory effect of the artery without endothelium to the new ON was more pronounced than that to IS-5-MN. The mechanism of the relaxant effect of the new compound consisted in the liberation of nitric-oxide (NO) which activated guanylate cyclase (GC), upon which accumulation of cyclic guanosine monophosphate (cGMP) occurred, which was the second messenger leading to relaxation. Tolerance to the frequent applications of the new compound was not observed, moreover a slight increase of the effect was detected in comparison with IS-5-MN for which tolerance was observed to a great extent. Clinically, the new ON could be favorable in all types of angina in comparison with the classical IS-5-MN.", publisher = "Georg Thieme Verlag Kg, Stuttgart", journal = "Arzneimittelforschung - Drug Research", title = "Comparison of the relaxant effects of a new oxime-nitrate derived from isosorbide-5-mononitrate and the parent drug", volume = "54", number = "4", pages = "195-202", doi = "10.1055/s-0031-1296959", url = "https://hdl.handle.net/21.15107/rcub_farfar_476" }
Stepanović-Petrović, R., Tokić-Vujošević, Z., Milovanović, S., Ceković, Z.,& Tomić, M.. (2004). Comparison of the relaxant effects of a new oxime-nitrate derived from isosorbide-5-mononitrate and the parent drug. in Arzneimittelforschung - Drug Research Georg Thieme Verlag Kg, Stuttgart., 54(4), 195-202. https://doi.org/10.1055/s-0031-1296959 https://hdl.handle.net/21.15107/rcub_farfar_476
Stepanović-Petrović R, Tokić-Vujošević Z, Milovanović S, Ceković Z, Tomić M. Comparison of the relaxant effects of a new oxime-nitrate derived from isosorbide-5-mononitrate and the parent drug. in Arzneimittelforschung - Drug Research. 2004;54(4):195-202. doi:10.1055/s-0031-1296959 https://hdl.handle.net/21.15107/rcub_farfar_476 .
Stepanović-Petrović, Radica, Tokić-Vujošević, Zorana, Milovanović, S, Ceković, Z, Tomić, Maja, "Comparison of the relaxant effects of a new oxime-nitrate derived from isosorbide-5-mononitrate and the parent drug" in Arzneimittelforschung - Drug Research, 54, no. 4 (2004):195-202, https://doi.org/10.1055/s-0031-1296959 ., https://hdl.handle.net/21.15107/rcub_farfar_476 .