Abstract
The effects of K+ channel openers (PCOs), NIP-121, levcromakalim and nicorandil, and the blockers of the specific binding sites for [3H]glibenclamide, ATP-sensitive K+ channel blocker, were investigated in rat brain and cardiac ventricle membrane preparations. When the microsomes were incubated with [3H]glibenclamide, the specific glibenclamide binding was fully inhibited by unlabeled glibenclamide (1 μM) and apamin (100 μM). However, the specific glibenclamide binding was not influenced by excess NIP-121, levcromakalim and nicorandil, although glibenclamide antagonized the increase in the 86Rb+ efflux by PCOs. On the other hand, the binding of [3H]glibenclamide after a long pre-incubation (60 min) at 37°C with NIP-121 and levcromakalim at pharmacological effective concentrations (10 nM to 1 μM) was significantly influenced. Both PCOs partially reduced both Kd and Bmax values of the specific [3H]- glibenclamide binding in a concentration-dependent manner that was not regulated by GTPγS. The doseeffect relationships for the Bmax''s of NIP-121 and levcromakalim seemed similar to those for vasorelaxation. These findings indicate that the pharmacological effect of PCO may be caused by the binding to its own specific sites but not to the specific sulfonylurea sites. The binding of PCOs may inhibit, in a negative allosteric manner the binding of sulfonylureas.
