Molecular mechanisms of the inhibitory effects of clonidine on vascular adenosine triphosphate-sensitive potassium channels.

BACKGROUND

We investigated the effects of the imidazoline-derived α2-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 (Kir6.2ΔC36 channels); and (4) mutant Kir6.2ΔC36 channels with diminished sensitivity to ATP (Kir6.2ΔC36-K185Q channels).

RESULTS

Clonidine (≥3 × 10(-8) M) inhibited native K(ATP) channel activity in cell-attached configurations with a half-maximal inhibitory concentration value of 1.21 × 10(-6) M and in inside-out configurations with a half-maximal inhibitory concentration value of 0.89 × 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 Kir6.2ΔC36 channel, and the Kir6.2ΔC36-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.