Adenosine activates ATP-sensitive potassium channels in arterial myocytes via A₂ receptors and cAMP-dependent protein kinase

The mechanism by which the endogenous vasodilator adenosine causes ATP- sensitive potassium (K(ATP)) channels in arterial smooth muscle to open was investigated by the whole-cell patch-clamp technique. Adenosine induced voltage-independent, potassium-selective currents, which were inhibited by glibenclamide, a blocker of KATP currents. Glibenclamide-sensitive currents were also activated by the selective adenosine A₂-receptor agonist 2-p-(2- carboxethyl)-phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride (CGS-21680), whereas 2-chloro-N⁶-cyclopentyladenosine (CCPA), a selective adenosine A₁-receptor agonist, failed to induce potassium currents. Glibenclamide-sensitive currents induced by adenosine and CGS-21680 were largely reduced by blockers of the cAMP-dependent protein kinase (Rp-cAMP[S], H-89, protein kinase A inhibitor peptide). Therefore, we conclude that adenosine can activate K(ATP) currents in arterial smooth muscle through the following pathway: (i) Adenosine stimulates A₂ receptors, which activates adenylyl cyclase; (ii) the resulting increase in intracellular cAMP stimulates protein kinase A, which, probably through a phosphorylation step, opens K(ATP) channels.