Abstract
PurposeSeveral clinical studies have demonstrated that angiotensin-converting enzyme inhibitors, but not angiotensin II receptor blockers (ARBs), reduce the risk of non-fatal myocardial infarction and cardiovascular mortality. We found that ARBs inhibited the activity of various cytochrome enzymes in arachidonic acid metabolism, resulting in decreased in vitro production of epoxyeicosatrienoic acids (EETs), which exhibit vasodilation and anti-inflammatory effects, and their subsequent metabolites, dihydroxyeicosatrienoic acids (DHETs). The present study examined the effects of ARBs on serum levels of EETs and DHETs in patients admitted to a cardiovascular center.MethodsA total of 223 patients were enrolled, of which 107 were exposed to ARBs in this study. ARB-free individuals were defined as the control group (n = 116). Serum levels of EETs and DHETs were measured by liquid chromatography–tandem mass spectrometry. Multiple linear regression analyses were carried out to identify covariates for total serum levels of EETs and DHETs.ResultsA significant negative association was observed between ARB use and serum EET and DHET levels (p = 0.034), whereas a significant positive association was observed between the estimated glomerular filtration rate (eGFR) and serum EET and DHET levels (p = 0.007). The median serum total EET and DHET level in the ARB group tended to become lower than that in the control group, although the difference was not significant.ConclusionARB use and eGFR were significantly associated with total serum levels of EETs and DHETs. Our results suggest that ARBs could affect the concentration of EETs in vivo.
Highlights
Cytochromes P450 (CYPs), 2C8, 2C9, and 2J2 metabolize arachidonic acid (AA) to four regioisomeric epoxyeicosatrienoic acids (EETs), 14,15, 11,12, 8,9, and 5,6-EET [1]
EETs are subsequently metabolized by soluble epoxide hydrolase [1] to the corresponding dihydroxyeicosatrienoic acids (DHETs), which are generally less biologically active compared to EETs [2], Oltmann et al [5] and Lu et al [6] reported that DHETs exhibit more potent vasodilatory effects than EETs
We investigated the effects of angiotensin II receptor blockers (ARBs) on serum levels of EETs and DHETs in patients admitted to a cardiovascular center
Summary
Cytochromes P450 (CYPs), 2C8, 2C9, and 2J2 metabolize arachidonic acid (AA) to four regioisomeric epoxyeicosatrienoic acids (EETs), 14,15-, 11,12-, 8,9-, and 5,6-EET [1]. Low levels of circulating total EETs and DHETs may theoretically increase the risk of cardiovascular events. Several clinical trials have suggested that ARBs and angiotensin-converting enzyme inhibitors (ACEIs) have a prophylactic effect against cardiovascular events [14,15,16,17,18,19,20]. Similar results have been reported by other researchers [26, 27]; it remains unclear whether ARBs reduce the production of EETs from AA in vivo. Given this background, we investigated the effects of ARBs on serum levels of EETs and DHETs in patients admitted to a cardiovascular center. We explored the covariates related to total EET and DHET serum levels using multiple linear regression analysis
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