Characterization of a beta‐adrenergically inhibited K+ current in rat cardiac ventricular cells.

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Abstract
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.

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