Arachidonic Acid Metabolites of CYP450 Enzymes and HIF-1α Modulate Endothelium-Dependent Vasorelaxation in Sprague-Dawley Rats under Acute and Intermittent Hyperbaric Oxygenation

Acetylcholine-induced vasorelaxation (AChIR) and responses to reduced pO(2) (hypoxia-induced relaxation (HIR), 0% O(2)) were assessed in vitro in aortic rings of healthy male Sprague-Dawley rats (N = 252) under hyperbaric (HBO(2)) protocols. The studied groups consisted of the CTRL group (untreated); the A-HBO(2) group (single HBO(2); 120 min of 100% O(2) at 2.0 bars); the 24H-HBO(2) group (examined 24 h after single exposure) and the 4D-HBO(2) group (four consecutive days of single HBO(2)). AChIR, sensitivity to ACh and iNOS expression were decreased in the A-HBO(2) group. HIR was prostanoid- and epoxyeicosatrienoic acid (EET)-mediated. HIF-1α expression was increased in the 24H-HBO(2) and 4D-HBO(2) groups. LW6 (HIF-1α inhibitor) decreased HIR in the 24H-HBO(2) group. HBO(2) affected the expression of COX-1 and COX-2. CYP2c11 expression was elevated in the 24H-HBO(2) and 4D-HBO(2) groups. Concentrations of arachidonic acid (AA) metabolites 14(15)-DiHET, 11(12)-DiHET and 8(9)-DiHET were increased in A-HBO(2) and 24H-HBO(2.) An increased concentration of 8(9)-EET was observed in the A-HBO(2) and 24h-HBO(2) groups vs. the CTRL and 4D-HBO(2) groups, and an increased concentration of 5(6)-DiHET was observed in the 24H-HBO(2) group vs. the 4D-HBO(2) group. The 20-HETE concentration was increased in the A-HBO(2) group. All were determined by LC-MS/MS of the aorta. The results show that AChIR in all groups is mostly NO-dependent. HIR is undoubtedly mediated by the CYP450 enzymes’ metabolites of AA, whereas HIF-1α contributes to restored HIR. Vasoconstrictor metabolites of CYP450 enzymes contribute to attenuated AChIR and HIR in A-HBO(2).