Hydrogen peroxide constricts rat arteries by activating Na+-permeable and Ca2+-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 Ca²⁺]_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 (H₂O₂) 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. Ca²⁺]_i and Na⁺]_i were measured with microfluorometry using Fura2-AM and SBFI-AM, respectively. We found that H₂O₂ (10 and 100 µM) increased arterial contraction, and nifedipine blocked the effects of H₂O₂ on isometric contraction. H₂O₂ increased Ca²⁺]_i as well as Na⁺]_i, and depolarised Em. Gd³⁺ (1 µM) blocked all these H₂O₂-induced effects including Em depolarisation and increases in Ca²⁺]_i and Na⁺]_i. Although both nifedipine (30?nM) and low Na⁺ bath solution completely prevented the H₂O₂-induced increase in Na⁺], they only partly inhibited the H₂O₂-induced effects on Ca²⁺]_i and Em. Taken together, the results suggested that H₂O₂ constricts rat arteries by causing Em depolarisation and VDCC_L 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.