Hydrogen peroxide constricts rat arteries by activating Na + -permeable and Ca 2+ -permeable cation channels.

Oxidative stress is associated with many cardiovascular diseases, such as hypertension and arteriosclerosis. Oxidative stress reportedly activates the L-type voltage-gated calcium channel (VDCCL ) and elevates [Ca2+ ]i in many cells. However, how oxidative stress activates VDCCL under clinical setting and the consequence for arteries are unclear. Here, we examined the hypothesis that hydrogen peroxide (H2 O2 ) regulates membrane potential (Em) by altering Na+ influx through cation channels, which consequently activates VDCCL to induce vasoconstriction in rat mesenteric arteries. To measure the tone of the endothelium-denuded arteries, a conventional isometric organ chamber was used. Membrane currents and Em were recorded by the patch-clamp technique. [Ca2+ ]i and [Na+ ]i were measured with microfluorometry using Fura2-AM and SBFI-AM, respectively. We found that H2 O2 (10 and 100 µM) increased arterial contraction, and nifedipine blocked the effects of H2 O2 on isometric contraction. H2 O2 increased [Ca2+ ]i as well as [Na+ ]i , and depolarized Em. Gd3+ (1 µM) blocked all these H2 O2 -induced effects including Em depolarization and increases in [Ca2+ ]i and [Na+ ]i . Although both nifedipine (30 nM) and low Na+ bath solution completely prevented the H2 O2 -induced increase in [Na+ ], they only partly inhibited the H2 O2 -induced effects on [Ca2+ ]i and Em. Taken together, the results suggested that H2 O2 constricts rat arteries by causing Em depolarization and VDCCL activation through activating Gd3+ -and nifedipine-sensitive, Na+ -permeable channels as well as Gd3+ -sensitive Ca2+ -permeable cation channels. We suggest that unidentified Na+ -permeable cation channels as well as Ca2+ -permeable cation channels may function as important mediators for oxidative stress-induced vascular dysfunction.