INHIBITION OF A FAST INWARDLY RECTIFYING POTASSIUM CONDUCTANCE BY BARBITURATES

Whole cell voltage damp recordings were used to study the effects of t wo barbiturates, methohexital and pentobarbital, on inwardly rectifyin g K+ currents in the plasma membrane of a rat basophilic granulocyte c ell 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 rectifi er is the only apparent voltage-dependent current in these cells. Step s to command potentials between +80 and -120 mV evoked only this stron gly rectifying, rapidly developing current at membrane potentials more hyperpolarized than the reversal potential for K+ ions. Extracellular Cs+ (10 mM) and Ba2+ (100 mu M and 1 mM) blocked this current in a re versible and voltage-dependent manner. The voltage threshold for activ ation of the inwardly rectifying K+ current is dependent an the extrac ellular K+ concentration as predicted by the Nernst equation. Methohex ital and pentobarbital reversibly inhibited the current in a concentra tion-dependent fashion with 50% inhibitory concentration (IC50) values of 145 mu M and 218 mu M respectively. The Hill slopes for both of th ese effects were approximately 1. The inhibition was not voltage depen dent. These results indicate that fast inwardly rectifying K+ channels are potential molecular targets for barbiturates and could explain so me of the diverse clinical effects of these drugs.