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 (VDCC _L ) and elevates [Ca ²⁺ ] _i in many cells. However, how oxidative stress activates VDCC _L under clinical setting and the consequence for arteries are unclear. Here, we examined the hypothesis that hydrogen peroxide (H ₂ O ₂ ) regulates membrane potential (Em) by altering Na ⁺ influx through cation channels, which consequently activates VDCC _L 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. [Ca ²⁺ ] _i and [Na ⁺ ] _i were measured with microfluorometry using Fura2-AM and SBFI-AM, respectively. We found that H ₂ O ₂ (10 and 100 µM) increased arterial contraction, and nifedipine blocked the effects of H ₂ O ₂ on isometric contraction. H ₂ O ₂ increased [Ca ²⁺ ] _i as well as [Na ⁺ ] _i , and depolarised Em. Gd ³⁺ (1 µM) blocked all these H ₂ O ₂ -induced effects including Em depolarisation and increases in [Ca ²⁺ ] _i and [Na ⁺ ] _i . Although both nifedipine (30 nM) and low Na ⁺ bath solution completely prevented the H ₂ O ₂ -induced increase in [Na ⁺ ], they only partly inhibited the H ₂ O ₂ -induced effects on [Ca ²⁺ ] _i and Em. Taken together, the results suggested that H ₂ O ₂ constricts rat arteries by causing Em depolarisation and VDCC _L activation through activating Gd ³⁺ -and nifedipine-sensitive, Na ⁺ -permeable channels as well as Gd ³⁺ -sensitive Ca ²⁺ -permeable cation channels. We suggest that unidentified Na ⁺ -permeable cation channels as well as Ca ²⁺ -permeable cation channels may function as important mediators for oxidative stress-induced vascular dysfunction.