Vulnerability of the retinal microvasculature to oxidative stress: ion channel-dependent mechanisms

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Abstract
Although oxidative stress is a hallmark of important vascular disorders such as diabetic retinopathy, it remains unclear why the retinal microvasculature is particularly vulnerable to this pathophysiological condition. We postulated that redox-sensitive ion channels may play a role. Using H2O2 to cause oxidative stress in microvascular complexes freshly isolated from the adult rat retina, we assessed ionic currents, cell viability, intracellular oxidants, and cell calcium by using perforated-patch recordings, trypan blue dye exclusion, and fura-2 fluorescence, respectively. Supporting a role for the oxidant-sensitive ATP-sensitive K (KATP) channels, we found that these channels are activated during exposure of retinal microvessels to H2O2. Furthermore, their inhibition by glibenclamide significantly lessened H2O2-induced microvascular cell death. Additional experiments established that by increasing the influx of calcium into microvascular cells, the KATP channel-mediated hyperpolarization boosted the vulnerability of these cells to oxidative stress. In addition to the KATP channel-dependent mechanism for increasing the lethality of oxidative stress, we also found that the vulnerability of cells in the capillaries, but not in the arterioles, was further boosted by a KATP channel-independent mechanism, which our experiments indicated involves the oxidant-induced activation of calcium-permeable nonspecific cation channels. Taken together, our findings support a working model in which both KATP channel-independent and KATP channel-dependent mechanisms render the capillaries of the retina particularly vulnerable to oxidative stress. Identification of these previously unappreciated mechanisms for boosting the lethality of oxidants may provide new targets for pharmacologically limiting damage to the retinal microvasculature during periods of oxidative stress.

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