Nox1 upregulates the function of vascular T-type calcium channels following chronic nitric oxide deficit
Date
2014
Authors
Howitt, Lauren
Matthaei, Klaus
Hill, Caryl
Drummond, Grant
Journal Title
Journal ISSN
Volume Title
Publisher
Springer
Abstract
Cardiovascular disease is characterised by reduced nitric oxide bioavailability resulting from oxidative stress. Our previous studies have shown that nitric oxide deficit per se increases the contribution of T-type calcium channels to vascular tone through increased superoxide from NADPH oxidase (Nox). The aim of the present study was therefore to identify the Nox isoform responsible for modulating T-type channel function, as T-type channels are implicated in several pathophysiological conditions involving oxidative stress. We evaluated T-channel function in skeletal muscle arterioles in vivo, using a novel T-channel blocker, TTA-A2 (3 μmol/L), which demonstrated no cross reactivity with L-type channels. Wild-type and Nox2 knockout (Nox2ko) mice were treated with the nitric oxide synthase inhibitor L-NAME (40 mg/kg/day) for 2 weeks. L-NAME treatment significantly increased systolic blood pressure and the contribution of T-type calcium channels to arteriolar tone in wild-type mice, and this was not prevented by Nox2 deletion. In Nox2ko mice, pharmacological inhibition of Nox1 (10 μmol/L ML171), Nox4 (10 μmol/L VAS2870) and Nox4-derived hydrogen peroxide (500 U/mL catalase) significantly reduced the effect of chronic nitric oxide inhibition on T-type channel function. In contrast, in wild-type mice, ML171 and VAS2870, but not catalase, reduced the contribution of T-type channels to vascular tone, suggesting a role for Nox1 and non-selective actions of VAS2870. We conclude that Nox1, but not Nox2 or Nox4, is responsible for the upregulation of T-type calcium channels elicited by chronic nitric oxide deficit. These data point to an important role for this isoform in increasing T-type channel function during oxidative stress.
Description
Keywords
Citation
Collections
Source
Pflugers Archives European Journal of Physiology
Type
Journal article
Book Title
Entity type
Access Statement
License Rights
DOI
10.1007/s00424-014-1548-5
Restricted until
2037-12-31