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Evidence for two-pore domain potassium channels in rat cerebral arteries

Departments of ¹Anesthesiology, ²Medicine (Cardiovascular Sciences), and ³Molecular Physiology and Biophysics, Baylor College of Medicine, ⁵Department of Biochemistry and Biological Sciences, University of Houston, Houston, Texas; and ⁴Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, Louisiana

Submitted 28 December 2005 ; accepted in final form 7 March 2006

Little is known about the presence and function of two-pore domain K⁺ (K_2P) channels in vascular smooth muscle cells (VSMCs). Five members of the K_2P channel family are known to be directly activated by arachidonic acid (AA). The purpose of this study was to determine 1) whether AA-sensitive K_2P channels are expressed in cerebral VSMCs and 2) whether AA dilates the rat middle cerebral artery (MCA) by increasing K⁺ currents in VSMCs via an atypical K⁺ channel. RT-PCR revealed message for the following AA-sensitive K_2P channels in rat MCA: tandem of P domains in weak inward rectifier K⁺ (TWIK-2), TWIK-related K⁺ (TREK-1 and TREK-2), TWIK-related AA-stimulated K⁺ (TRAAK), and TWIK-related halothane-inhibited K⁺ (THIK-1) channels. However, in isolated VSMCs, only message for TWIK-2 was found. Western blotting showed that TWIK-2 is present in MCA, and immunohistochemistry further demonstrated its presence in VSMCs. AA (10–100 µM) dilated MCAs through an endothelium-independent mechanism. AA-induced dilation was not affected by inhibition of cyclooxygenase, epoxygenase, or lipoxygenase or inhibition of classical K⁺ channels with 10 mM TEA, 3 mM 4-aminopyridine, 10 µM glibenclamide, or 100 µM Ba²⁺. AA-induced dilations were blocked by 50 mM K⁺, indicating involvement of a K⁺ channel. AA (10 µM) increased whole cell K⁺ currents in dispersed cerebral VSMCs. AA-induced currents were not affected by inhibitors of the AA metabolic pathways or blockade of classical K⁺ channels. We conclude that AA dilates the rat MCA and increases K⁺ currents in VSMCs via an atypical K⁺ channel that is likely a member of the K_2P channel family.

arachidonic acid; arachidonic acid-stimulated potassium channel; membrane potential; hyperpolarization; vasodilation; electrophysiology; TREK-1; TREK-2; TRAAK; THIK-1; TWIK-2

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