© 1997 by European Society of Cardiology
Copyright © 1997, European Society of Cardiology
Endothelin-1 inhibition of cardiac ATP-sensitive K+ channels via pertussis-toxin-sensitive G-proteins
The Department of Cardiovascular Medicine, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto, 606-01, Japan
Objective: Secretion of endothelin-1 (ET-1) and activation of cardiac ATP-sensitive K+ (KATP) channels are facilitated under myocardial metabolic stress. The aim of this study was to investigate the effects of ET-1 on KATP channels and to assess underlying mechanisms in ventricular myocytes. Methods: Single channel currents were measured with the voltage-clamp technique in cell-attached patches from enzymatically-isolated single guinea pig ventricular myocytes. In some experiments, the open-cell-attached mode was employed by permeating the membrane with streptolysin-O. Results: ET-1 concentration-dependently inhibited single KATP channel currents, which had been activated by metabolic poisoning, with an IC50 of 3.8 ± 0.7 pM. BQ-123, an ETA receptor-selective antagonist, reduced the effects of ET-1. ET-1 effects were largely abolished in the myocytes pre-incubated with pertussis toxin. In the open-cell-attached mode, where the intracellular ATP concentration ([ATP]) could be virtually controlled, the effects of ET-1 were abolished. Muscarinic receptor stimulation inhibited the channels in a similar manner to ET-1, whereas β-adrenoceptor stimulation accelerated channel activation. By analogy, ouabain also inhibited KATP channel activity under metabolic stress presumably because inhibition of the Na+/K+ pump spares subsarcolemmal ATP. ET-1 inhibited the KATP channels that had been reactivated in the continuous presence of ouabain. Conclusions: ET-1 reversibly inhibited KATP channels. This effect appears to be mediated by an increase in subsarcolemmal [ATP] which results from inhibition of adenylate cyclase activities through PTX-sensitive G-proteins coupled to ETA receptors.
KEYWORDS Endothelin-1; Carbachol; Ouabain; G-proteins; Isoproterenol; Potassium channel; ATP-sensitive; Guinea pig; ventricular myocytes
* Corresponding author. Division of Cardiac Electrophysiology, The Department of Cardiovascular Medicine, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-01, Japan. Tel. +81 75 751-3196; Fax +81 75 761-9716; E-mail: horie@kuhp.kyoto-u.ac.jp
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