alpha 1-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.
Effects of alpha 1-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 microM) markedly shortened the action potential duration (APD) (to 51 +/- 2% and 40 +/- 5% of each control value). Addition of 100 microM methoxamine, an alpha 1-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 microM prazosin (alpha 1-antagonist) and 100 nM WB4101 (alpha 1A-antagonist) but not by 10 microM chloroethylclonidine (alpha 1B-antagonist). In papillary muscles exposed to a hypoxic, glucose-free solution, APD declined gradually. In the presence of 100 microM methoxamine or 10 microM 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 microM), thereby suggesting that these KCOs activate IK.ATP. Methoxamine (100 microM) significantly inhibited the nicorandil-induced IK.ATP by 18 +/- 5% and the cromakalim-induced IK.ATP by 16 +/- 2%. 4 beta-Phorbol 12-myristate 13-acetate (100 nM), a protein kinase C activator, failed to mimic the alpha 1-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 micrograms/ml), an inositol 1,4,5-trisphosphate (IP3)-dependent Ca2+ release inhibitor, nor IP3 (20 microM) plus inositol 1,3,4,5-tetrakisphosphate (IP4 5 microM) could affect the inhibitory action of methoxamine. In conclusion, alpha 1A-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 alpha 1A-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.
Takizawa
T
T
Department of Pharmacology, Chiba University School of Medicine, Japan.
Hara
Y
Y
Saito
T
T
Masuda
Y
Y
Nakaya
H
H
D000200:Action Potentials / Q000187:drug effects; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D002478:Cells, Cultured; D019806:Cromakalim; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology*; D006352:Heart Ventricles / Q000187:drug effects; D000860:Hypoxia / Q000503:physiopathology; D008297:Male; D008729:Methoxamine / Q000494:pharmacology*; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D020108:Nicorandil; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000819:agonists*; D011758:Pyrroles / Q000494:pharmacology; D016276:Ventricular Function
D000316:Adrenergic alpha-Agonists; D001578:Benzopyrans; D015221:Potassium Channels; D011758:Pyrroles; D019806:Cromakalim; D009536:Niacinamide; D020108:Nicorandil; D008729:Methoxamine