α1-Adrenoceptor Stimulation Partially Inhibits ATP-Sensitive K+ Current in Guinea Pig Ventricular Cells: Attenuation of the Action Potential Shortening Induced by Hypoxia and K+ Channel Openers

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Abstract
Effects of α1-adrenoceptor stimulation on the action potential shortening produced by K+ channel openers (KCOs) or hypoxia and on the ATP-sensitive K+ current (IK.ATP) activated by KCOs were examined in guinea-pig ventricular cells by using conventional microelectrode and patch-clamp techniques. In papillary muscles, nicorandil (1 mM) or cromakalim (30 μM) markedly shortened the action potential duration (APD) (to 51 ± 2% and 40 ± 5% of each control value). Addition of 100 μM methoxamine, an α1-adrenoceptor agonist, partially but significantly reversed the KCOs-induced APD shortening (to 69 ± 3% and 50 ± 4% of each control value). The APD-prolonging effect of methoxamine was antagonized by 1 μM prazosin (α1-antagonist) and 100 nM WB4101 (α1A-antagonist) but not by 10 μM chloroethylclonidine (α1B-antagonist). In papillary muscles exposed to a hypoxic, glucose-free solution, APD declined gradually. In the presence of 100 μM methoxamine or 10 μM glibenclamide, the hypoxia-induced action potential shortening was significantly inhibited. In single ventricular myocytes, the KCOs increased a steady-state outward current that was abolished by glibenclamide (1 μM), thereby suggesting that these KCOs activate IK.ATP. Methoxamine (100 μM) significantly inhibited the nicorandil-induced IK.ATP by 18 ± 5% and the cromakalim-induced IK.ATP by 16 ± 2%. 4β-Phorbol 12-myristate 13-acetate (100 nM), a protein kinase C activator, failed to mimic the α1-adrenoceptor-mediated inhibition of the nicorandil-induced outward current. Staurosporine (30 nM), a protein kinase C inhibitor, also failed to affect the partial inhibition of IK.ATP by methoxamine. Neither intracellular loading of heparin (100 μg/ml), an inositol 1,4,5-trisphosphate (IP3)-dependent Ca2+ release inhibitor, nor IP3 (20 μM) plus inositol 1,3,4,5-tetrakisphosphate (IP4 5 μM) could affect the inhibitory action of methoxamine. In conclusion, α1A-adrenergic stimulation partially inhibits IK.ATP in cardiac cells. Neither protein kinase C activation nor IP3 formation appears to be involved in the partial inhibition of IK.ATP. The α1A-adrenoceptor-mediated inhibition of IK.ATP may be deleterious for ischemic myocardium and partly offset the cardioprotective effect of KCOs because attenuation of action potential shortening may potentially increase Ca2+ influx in ischemic cells.