Vascular biotransformation of organic nitrates is independent of cytochrome P450 monooxygenases

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 ischaemic heart disease. These compounds are prodrugs which release their nitrovasodilators upon enzymic bioactivation by aldehyde dehydrogenase (ALDH2) cytochromes P450 (CYP). Whereas ALDH2 is known to directly activate organic vessels, contribution vascular CYPs unknown was studied here. Experimental Approach As all depend on cytochrome reductase (POR) electron donor, we generated smooth muscle cell-specific, inducible knockout mouse POR (smcPOR?/?) investigate POR/CYP biotransformation nitrates. Key Results Microsomes containing recombinant expressed human tissues released nitrite from NTG PETN with CYP2C9 CYP2C8 being most efficient. SFK525, CYP suicide inhibitor, blocked this effect. smcPOR?/? mice exhibited no obvious cardiovascular phenotype (normal cardiac weight endothelium-dependent relaxation) plasma production similar control (CTL) animals. NTG- PETN-induced relaxation isolated endothelium-intact endothelium-denuded vessels were identical between CTL smcPOR?/?. Likewise, aortic rings not affected deletion cells (SMCs). In contrast, inhibition benomyl (10 ?M) inhibited NTG-induced relaxation. Deletion did modulate response. Conclusions Implications Our data suggest that metabolism does contribute pharmacological function