3‐hydroxybutyrate blocks the transient K+ outward current in myocardial mouse cells in a stereoselective fashion.

Abstract

1. Mouse ventricular myocytes develop a large transient K+ outward current (I(TO)) which accelerates repolarization and is a crucial determinant for the regulation of the action potential duration at various heart rates. The effect of 3-hydroxybutyrate on I(TO) was investigated under voltage- and current-clamp conditions. 2. The drug blocked I(TO) in a stereoselective manner with the L-enantiomer being the effective and the D-enantiomer, the ineffective form. The blocking action of the L-enantiomer was established immediately and it could be completely washed out within several tens of seconds. 3. The dose-response characteristic for the peak I(TO) showed a strict 1:1 binding of the drug to the receptor with a concentration of half-maximum effect of 2.1 mmol l(-1). 4. The action of L-hydroxybutyrate was voltage independent, did not need channel opening and preferentially affected the slow component of both inactivation and recovery from inactivation. 5. At the high concentration of 20 mmol l(-1) the optically inactive form, the racemate, did not affect I(TO), indicating that the ineffective D-enantiomer interacts with the channels at much lower concentrations. 6. At a concentration of 10 mmol l(-1), L-hydroxybutyrate prolonged the action potential by 218 +/- 26 and 127 +/- 10% (means +/- S.E.M.) at 50 and 90% repolarization, respectively. 7. It is concluded that the non-physiological L-hydroxybutyrate is a novel type of blocker of I(TO), It interacts either with the channel itself, or with a receptor protein closely related to the channel and preferentially affects slow inactivation.