Inhibition of a Fast Inwardly Rectifying Potassium Conductance by Barbiturates

Abstract

Whole cell voltage clamp recordings were used to study the effects of two barbiturates, methohexital and pentobarbital, on inwardly rectifying K+ currents in the plasma membrane of a rat basophilic granulocyte cell line (RBL-1). Inwardly rectifying K+ currents are responsible for maintaining the resting membrane potential in a variety of cell types including skeletal and cardiac muscle, neurons, glia, blood cells, and endothelial cells. RBL-1 cells are unusual because the inward rectifier is the only apparent voltage-dependent current in these cells. Steps to command potentials between + 80 and -120 mV evoked only this strongly rectifying, rapidly developing current at membrane potentials more hyperpolarized than the reversal potential for K' ions. Extracellular Cs+ (10 mM) and Ba2+ (100 microM and 1 mM) blocked this current in a reversible and voltage-dependent manner. The voltage threshold for activation of the inwardly rectifying K+ current is dependent on the extracellular K+ concentration as predicted by the Nernst equation. Methohexital and pentobarbital reversibly inhibited the current in a concentration-dependent fashion with 50% inhibitory concentration (IC50) values of 145 microM and 218 microM respectively. The Hill slopes for both of these effects were approximately 1. The inhibition was not voltage dependent. These results indicate that fast inwardly rectifying K+ channels are potential molecular targets for barbiturates and could explain some of the diverse clinical effects of these drugs.