Objectives: To investigate whether hyperbaric oxygenation (HBO) modulates vascular reactivity to angiotensin II (ANG II) and angiotensin-(1-7) (ANG-(1-7)) in healthy and diabetic rats and to assess the role of epoxy eicosatrienoic acids (EETs) and CYP enzymes in the modulation of vascular reactivity by HBO. Additionally, the goal was to examine if possible changes in arterial blood pressure and oxidative stress play a role in such modulation of vascular responses. Methods: The study was conducted using isolated thoracic aortic ring preparations to test vascular reactivity (functional studies) to ANG II and ANG-(1-7) in healthy and diabetic rats (treated with an intermittent HBO protocol compared to nontreated), and using a highly selective inhibitor of EETs synthesis (MS-PPOH) to assess the functionl role of EETs. Furthermore, in vivo studies of HBO effects on arterial blood pressure were conducted, as well as molecular studies of the effects of HBO on oxidative stress indicators, serum concentration of ANG-(1-7), mRNA expression of CYP enzymes (quantitative PCR) and protein expression of CYP enzymes (Western blot) in healthy and diabetic rats. With the use of streptozocin, an animal model of type 1 diabetes was caused in Sprague-Dawley rats. Results: HBO did not significantly change aortic reactivity to ANG II alone in healthy and diabetic rats, but vascular responses to the combination of ANG II + ANG-(1-7) was significantly lower compared to ANG II contractions in healthy HBO rats, whereas such a difference was not present in untreated rats. HBO significantly increased aortic responses to ANG-(1-7) alone (after precontraction with noradrenaline) in healthy and diabetic animals. MS-PPOH reversed all effects of HBO on facilitation of vascular responses to ANG-(1-7). There were no significant changes in arterial pressure, oxidative stress and serum ANG-(1-7) levels. HBO had a tendency to increase CYP enzyme expression, and a statistically significant increase of mRNA expression was measured for CY4A1 in healthy and CYP2J3 in diabetic rats, while protein expression was significantly increased by HBO for CYP2C11 in diabetic rats. Conclusion: HBO significantly increases vascular responses to ANG-(1-7) , what could explain some of the observed positive effects of HBO in pathologic conditions. EETs seem to play an important role in the mechanism of this modulation. HBO increases the expression of specific CYP isoforms, but it is also possible that it increaees the vascular sensitivity to EETs. The changes in vascular reactivity were not a consequence of a possible change in arterial pressure, oxidative stress or ANG-(1-7) blood levels. HBO does not significantly alter reactivity to ANG II in either healthy or diabetic rats.