Molecular Mechanisms of the Inhibitory Effects of Clonidine on Vascular Adenosine Triphosphate-Sensitive Potassium Channels

BACKGROUND: We investigated the effects of the imidazoline-derived alpha 2-adrenoceptor agonist clonidine on vascular adenosine triphosphate-sensitive potassium (K(ATP)) channel activity in rat vascular smooth muscle cells and recombinant vascular K(ATP) channels transiently expressed in COS-7 cells. METHODS: Using the patch-clamp method, we investigated the effects of clonidine on the following: (1) native vascular K(ATP) channels; (2) recombinant K(ATP) channels with different combinations of various types of inwardly rectifying potassium channel (Kir6.0 family: Kir6.1, 6.2) and sulfonylurea receptor (SUR1, 2A, 2B) subunits; (3) SUR-deficient channels derived from a truncated isoform of the Kir6.2 subunit (Kir6.2 Delta C36 channels); and (4) mutant Kir6.2 Delta C36 channels with diminished sensitivity to ATP (Kir6.2 Delta C36-K185Q channels). RESULTS: Clonidine (>= 3 x 10(-8) M) inhibited native K(ATP) channel activity in cell-attached configurations with a half-maximal inhibitory concentration value of 1.21 x 10(-6) M and in inside-out configurations with a half-maximal inhibitory concentration value of 0.89 x 10(-6) M. With similar potency, clonidine (10(-6) or 10(-3) M) also inhibited the activities of various recombinant SUR/Kir6.0 K(ATP) channels, the Kir6.2 Delta C36 channel, and the Kir6.2 Delta C36-K185Q channel. CONCLUSIONS: Clinically relevant concentrations of clonidine inhibit K(ATP) channel activity in vascular smooth muscle cells. This inhibition seems to be the result of its effect on the Kir6.0 subunit and not on the SUR subunit. (Anesth Analg 2011;113:1374-80)