A redox-based O2 sensor in rat pulmonary vasculature.

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Abstract
The effector mechanism of hypoxic pulmonary vasoconstriction (HPV) involves K+ channel inhibition with subsequent membrane depolarization. It remains uncertain how hypoxia modulates K+ channel activity. The similar effects of hypoxia and mitochondrial electron transport chain (ETC) inhibitors on metabolism and vascular tone suggest a common mechanism of action. ETC inhibitors and hypoxia may alter cell redox status by causing an accumulation of electron donors from the Krebs cycle and by decreasing the production of activated O2 species (AOS) by the ETC. We hypothesized that this shift toward a more reduced redox state elicits vasoconstriction by inhibition of K+ channels. Pulmonary artery pressure and AOS, measured simultaneously using enhanced chemiluminescence, were studied in isolated perfused rat lungs during exposure to hypoxia, proximal ETC inhibitors (rotenone and antimycin A), and a distal ETC inhibitor (cyanide). Patch-clamp measurements of whole-cell K+ currents were made on freshly isolated rat pulmonary vascular smooth muscle cells during exposure to hypoxia and ETC inhibitors. Hypoxia, rotenone, and antimycin A decreased lung chemiluminescence (-62 +/- 12, -46 +/- 7, and -148 +/- 36 counts/0.1 s, respectively) and subsequently increased pulmonary artery pressure (+14 +/- 2, +13 +/- 3, and +21 +/- 3 mm Hg, respectively). These agents reversibly inhibited an outward, ATP-independent, K+ current in pulmonary vascular smooth muscle cells. Antimycin A and rotenone abolished subsequent HPV. In contrast, cyanide increased AOS and did not alter K+ currents or inhibit HPV. The initial effect of rotenone, antimycin A, and hypoxia was a change in redox status (evident as a decrease in production of AOS). This was associated with the reversible inhibition of an ATP-independent K+ channel and vasoconstriction. These findings are consistent with the existence of a redox-based O2 sensor in the pulmonary vasculature.

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