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Vascular biotransformation of organic nitrates is independent of cytochrome P450 monooxygenases
- Source :
- British Journal of Pharmacology. 178:1495-1506
- Publication Year :
- 2021
- Publisher :
- Wiley, 2021.
-
Abstract
- Background and Purpose Organic nitrates such as nitroglycerin (NTG) or pentaerythritol tetranitrate (PETN) have been used for over a century in the treatment of angina or ischaemic heart disease. These compounds are prodrugs which release their nitrovasodilators upon enzymic bioactivation by aldehyde dehydrogenase (ALDH2) or cytochromes P450 (CYP). Whereas ALDH2 is known to directly activate organic nitrates in vessels, the contribution of vascular CYPs is unknown and was studied here. Experimental Approach As all CYPs depend on cytochrome P450 reductase (POR) as electron donor, we generated a smooth muscle cell-specific, inducible knockout mouse of POR (smcPOR−/−) to investigate the contribution of POR/CYP to vascular biotransformation of organic nitrates. Key Results Microsomes containing recombinant CYPs expressed in human vascular tissues released nitrite from NTG and PETN with CYP2C9 and CYP2C8 being most efficient. SFK525, a CYP suicide inhibitor, blocked this effect. smcPOR−/− mice exhibited no obvious cardiovascular phenotype (normal cardiac weight and endothelium-dependent relaxation) and plasma and vascular nitrite production was similar to control (CTL) animals. NTG- and PETN-induced relaxation of isolated endothelium-intact or endothelium-denuded vessels were identical between CTL and smcPOR−/−. Likewise, nitrite release from organic nitrates in aortic rings was not affected by deletion of POR in smooth muscle cells (SMCs). In contrast, inhibition of ALDH2 by benomyl (10 μM) inhibited NTG-induced nitrite production and relaxation. Deletion of POR did not modulate this response. Conclusions and Implications Our data suggest that metabolism by vascular CYPs does not contribute to the pharmacological function of organic nitrates.
- Subjects :
- 0301 basic medicine
Aldehyde dehydrogenase
Pharmacology
Mice
Nitroglycerin
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Cytochrome P-450 Enzyme System
Animals
Pentaerythritol Tetranitrate
ddc:610
Nitrite
Biotransformation
Vascular tissue
Nitrates
biology
Chemistry
Cytochrome P450
Cytochrome P450 reductase
Metabolism
Monooxygenase
030104 developmental biology
biology.protein
Microsome
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 14765381 and 00071188
- Volume :
- 178
- Database :
- OpenAIRE
- Journal :
- British Journal of Pharmacology
- Accession number :
- edsair.doi.dedup.....353d832d418fe3da2c3d0a668ba29b98
- Full Text :
- https://doi.org/10.1111/bph.15362