TY  - JOUR
A1  - López Sciarra, Melina
A1  - Malacarne, Pedro Felipe
A1  - Gajos-Draus, Anna
A1  - Ding, Xinxin
A1  - Daiber, Andreas
A1  - Lundberg, Jon O.
A1  - Offermanns, Stefan
A1  - Brandes, Ralf
A1  - Rezende Felipe, Flávia Figueiredo de
T1  - Vascular biotransformation of organic nitrates is independent of cytochrome P450 monooxygenases
T2  - British journal of pharmacology
N2  - 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.
KW  - ALDH2
KW  - cytochrome P450 enzymes
KW  - cytochrome P450 reductase
KW  - nitroglycerin
KW  - organic nitrates
KW  - pentaerythritol tetranitrate
KW  - POR
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/62227
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-622273
SN  - 1476-5381
N1  - This study was supported by the Deutsche Forschungsgemeinschaft “Vaskuläre Funktion der Cytochrom P450-Reduktase (POR)” to F.R., the Faculty of Medicine, Goethe-Universität, Frankfurt am Main, Germany (Forschungsförderung to F.R.), and the Heinrich und Fritz-Riese Stiftung to F.R. Open access funding enabled and organized by Projekt DEAL.

R.P.B. provided conceptual ideas and funding and wrote the manuscript; F.R. provided conceptual ideas and funding and wrote the manuscript. All authors read, revised, and approved the manuscript
VL  - 178
IS  - 7
SP  - 1495
EP  - 1506
PB  - Wiley
CY  - Malden, MA
ER  -