CO-04: Aging altered epoxyeicosatrienoic acid-mediated regulation of peripheral conduit artery diameter at rest and during sustained flow-mediated dilatation

Abstract

Background We evaluated the evolution of NO and CYP450 epoxygenases-derived epoxyeicosatrienoic acids (EETs) availability in conduit arteries during aging. Methods Radial artery diameter and mean wall shear stress were determined in 83 subjects (19 to 71 years old) at rest and during sustained endothelium-dependent flow-mediated dilatation induced by hand skin heating. The role of EETs and NO was assessed using the brachial infusion of inhibitors of cytochrome P450 epoxygenases (fluconazole) and NO-synthase (L-NMMA). Results Aging increased the reduction in basal arterial diameter induced by L-NMMA and nitrite plasma levels, an indicator of NO bioavailability. At the opposite, aging decreased EETs plasma levels and tended to reduce the basal vasoconstriction induced by fluconazole. Moreover, aging blunted the synergistic vasoconstricting effect of L-NMMA+fluconazole. Furthermore, the magnitude of flow-mediated dilatation was independently and negativelyrelated with age, together with baseline diameter and systolic blood pressure, and positively correlated with shear stress variation during heating. The increase in local nitrite level during heating and the decrease in flow-mediated dilatation induced by L-NMMA were not affected by aging. In contrast, aging tended to reduce the release of EETs and reduced the inhibitory effect of fluconazole alone and combined with L-NMMA on flow-mediated dilatation. Conclusions These results show that aging primarily impairs EETs availability and alters NO/EETs balance, contributing to promote endothelial dysfunction at the level of peripheral conduit arteries.