Abstract Body: Background:
Endothelium-derived hyperpolarizing factor (EDHF) plays an important role in regulating vascular tone in resistance arteries and contributes to the control of peripheral vascular resistance in cardiovascular diseases such as hypertension. Hydrogen peroxide (H₂O₂) has been proposed as a candidate EDHF that activates voltage-gated K⁺ (Kv) channels in vascular smooth muscle through redox-dependent mechanisms. However, the mechanisms underlying vessel-specific differences in H₂O₂ signaling remain poorly understood. Because Kv channel activation by H₂O₂ depends on redox-sensitive processes, we hypothesized that intrinsic differences in glutathione-dependent redox buffering between large and small arteries determine the effectiveness of H₂O₂-EDHF signaling.
Methods and Results:
Vascular reactivity, whole-cell Kv currents, and glutathione redox status were examined in rat thoracic aorta and mesenteric arteries. In endothelium-intact mesenteric arteries, acetylcholine-induced relaxation was partially inhibited by catalase and nitric oxide synthase inhibition, indicating a significant contribution of H₂O₂-dependent EDHF. In contrast, relaxation in the aorta was almost entirely nitric oxide-dependent. Patch-clamp recordings revealed that H₂O₂ enhanced Kv currents in mesenteric arterial smooth muscle cells but produced minimal activation in aortic smooth muscle cells. Analysis of glutathione redox status demonstrated that the aorta contained significantly lower total glutathione levels and a reduced GSH/GSSG ratio compared with mesenteric arteries, indicating a more oxidized basal redox environment. These findings suggest that redox-sensitive Kv channels in the aorta may exist in a near-maximally oxidized state, thereby limiting further activation by H₂O₂.
Conclusions:
Large conduit arteries exist in an intrinsically oxidized redox environment that limits H₂O₂-dependent Kv channel activation and EDHF signaling. Basal vascular redox state may therefore be an important determinant of vessel-specific vasodilatory signaling and vascular dysfunction in cardiovascular disease.