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Nox2‐derived superoxide does not contribute to oxidative stress‐induced vascular upregulation of T‐type channel function (893.6)

Cardiovascular disease is characterised by reduced nitric oxide (NO) and increased oxidative stress. We have shown that these conditions increase the expression and contribution of T‐type channels to vascular tone through increased bioavailability of reactive oxygen species produced from NADPH oxidase (Nox). As Nox2‐generated superoxide has been causally implicated in several vascular disease models, we investigated whether Nox2 was also responsible for upregulation of T‐type channel function in cremaster arterioles in vivo, using wildtype (WT) and Nox2‐deficient mice (Nox2KO). We first validated a novel T‐type channel antagonist, TTA‐A2 (3µM; provided by Merck and Co, Inc) which demonstrated no cross reactivity with L‐type channel function in these arterioles. In both WT and Nox2KO mice, acute inhibition of NO with L‐NAME (10µM) significantly increased the T‐type contribution to vascular tone. Chronic L‐NAME treatment (40mg/kg/day) for 2 weeks significantly increased blood pressure of both WT and Nox2KO mice, as well as the T‐type channel component of arteriolar tone. Pharmacological inhibition of Nox1 (10µM ML171) and Nox4 (10µM VAS2870) together reversed the effect of chronic L‐NAME on T‐type channel function in Nox2KO mice. We conclude that Nox2‐generated superoxide is not responsible for the upregulation of T‐type calcium channels elicited by oxidative stress.