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Effects of hypoxia, anoxia, and metabolic inhibitors on K_ATP channels in rat femoral artery myocytes

Department of Human Anatomy and Cell Biology, School of Biomedical Sciences, Liverpool University, Liverpool, United Kingdom

Submitted 19 October 2005 ; accepted in final form 12 February 2006

Vascular ATP-sensitive potassium (K_ATP) channels have an important role in hypoxic vasodilation. Because K_ATP channel activity depends on intracellular nucleotide concentration, one hypothesis is that hypoxia activates channels by reducing cellular ATP production. However, this has not been rigorously tested. In this study we measured K_ATP current in response to hypoxia and modulators of cellular metabolism in single smooth muscle cells from the rat femoral artery by using the whole cell patch-clamp technique. K_ATP current was not activated by exposure of cells to hypoxic solutions (PO₂ 35 mmHg). In contrast, voltage-dependent calcium current and the depolarization-induced rise in intracellular calcium concentration ([Ca²⁺]_i) was inhibited by hypoxia. Blocking mitochondrial ATP production by using the ATP synthase inhibitor oligomycin B (3 µM) did not activate current. Blocking glycolytic ATP production by using 2-deoxy-D-glucose (5 mM) also did not activate current. The protonophore carbonyl cyanide m-chlorophenylhydrazone (1 µM) depolarized the mitochondrial membrane potential and activated K_ATP current. This activation was reversed by oligomycin B, suggesting it occurred as a consequence of mitochondrial ATP consumption by ATP synthase working in reverse mode. Finally, anoxia induced by dithionite (0.5 mM) also depolarized the mitochondrial membrane potential and activated K_ATP current. Our data show that: 1) anoxia but not hypoxia activates K_ATP current in femoral artery myocytes; and 2) inhibition of cellular energy production is insufficient to activate K_ATP current and that energy consumption is required for current activation. These results suggest that vascular K_ATP channels are not activated during hypoxia via changes in cell metabolism. Furthermore, part of the relaxant effect of hypoxia on rat femoral artery may be mediated by changes in [Ca²⁺]_i through modulation of calcium channel activity.

smooth muscle; ion channels; potassium channels

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