Characterization of a beta-adrenergically inhibited K+ current in rat cardiac ventricular cells.
1. The electrophysiological properties and beta-adrenergic regulation of a non-inactivating K+ current were studied using the whole-cell patch-clamp technique (22 +/- 2 degrees C) in adult rat ventricular cells. 2. In the presence of 4-aminopyridine, an inhibitor of the rapidly inactivating current, the depolarization-activated current consisted only of a slowly decaying outward current (IK). The presence of a non-inactivating current (ISS) was revealed when analysing inactivation curves. 3. IK and ISS were both sensitive to 50 mM tetraethylammonium and 10 mM 4-aminopyridine inhibition. IK was totally blocked by 100 microM clofilium, while ISS was not inhibited but rather enhanced by this class III anti-arrhythmic agent. 4. Unlike IK, ISS was only slightly decreased by depolarizing prepulses and it did not show time-dependent inactivation when measured during 500 ms depolarizations. 5. ISS was decreased by the beta-adrenergic agonist isoprenaline (1 microM). Forskolin (10 microM) mimicked the effects of isoprenaline. The non-specific beta-adrenergic antagonist, propranolol (3 microM), and a specific beta 1-adrenergic antagonist, CGP 20712A (0.3 microM), both prevented the effects of isoprenaline. Cell perfusion with 100 microM PKI6-22, a peptide inhibitor of the cyclic AMP-dependent protein kinase, reduced or abolished the effects of isoprenaline. 6. The dose-response curve for the inhibition of ISS by isoprenaline was positioned to the left of that for the calcium current. The threshold dose and the dose giving 50% of the maximal effect were, respectively, 0.1 and 0.21 nM for ISS and 1 and 4.3 nM for ICa. 7. In view of the high sensitivity of ISS to isoprenaline, its possible physiological effect was evaluated on action potential duration during beta-adrenergic stimulation. At 1 nM, a concentration that did not increase ICa, isoprenaline induced a significant prolongation of action potential duration as a consequence of ISS inhibition. With 1 microM isoprenaline, the action potential was further prolonged, due largely to an evoked increase in ICa. 8. In conclusion, a K+ current displaying a weak voltage-dependent inactivation is present in rat ventricular cells. It is inhibited by stimulation of beta 1-adrenergic receptors and is highly sensitive to phosphorylation by protein kinase A. This current may play an important role in the neuromodulation of excitation-contraction coupling.
Scamps
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Laboratoire de Physiopathologie Cardiovasculaire, INSERM U-390, Centre Hospitalier Universitaire Arnaud de Villeneuve, Montpellier, France.
D015761:4-Aminopyridine / Q000494:pharmacology; D058665:Adrenergic beta-1 Receptor Agonists; D058671:Adrenergic beta-1 Receptor Antagonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D004594:Electrophysiology; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000502:physiology*; D013757:Tetraethylammonium Compounds / Q000494:pharmacology
D058665:Adrenergic beta-1 Receptor Agonists; D058671:Adrenergic beta-1 Receptor Antagonists; D000318:Adrenergic beta-Agonists; D000889:Anti-Arrhythmia Agents; D015221:Potassium Channels; D000644:Quaternary Ammonium Compounds; D011943:Receptors, Adrenergic, beta; D013757:Tetraethylammonium Compounds; C022799:clofilium; D015761:4-Aminopyridine; D007545:Isoproterenol