Identical inhibitory modulation of A-type potassium currents by dihydropyridine calcium channel agonists and antagonists

B Mlinar and JJ Enyeart

Department of Pharmacology, Ohio State University College of Medicine, Columbus 43210-1239.

We have studied the interaction of dihydropyridine (DHP) Ca2+ channel agonists and antagonists with A-type K+ channels in whole-cell patch- clamp recordings from bovine adrenal zona fasciculata cells. At concentrations from 1 to 100 microM, DHP antagonists [nimodipine and (+)-Bay K 8644] and agonists [(-)-Bay K 8644 and RS 30026] each reversibly reduced A-type K+ current (IA) amplitude and markedly accelerated the apparent rate of IA inactivation. Unlike their actions on Ca2+ channels, the effects of DHP agonists and antagonists on IA were qualitatively indistinguishable. Inhibition of IA by DHPs was not accompanied by changes in the voltage-dependent steady state inactivation of IA or the kinetics of recovery subsequent to repolarization. The effects of DHPs on peak IA and inactivation kinetics were not use dependent. The DHPs were much less effective in cells where fast N-type inactivation had spontaneously diminished with time. These actions of DHPs on IA are in marked contrast to their voltage-dependent modulation of L-type Ca2+ currents, indicating that fundamentally different mechanisms are involved. Rather than directly occluding A-type K+ channels, the drugs may enhance the voltage- independent rate of inactivation. This could occur through interaction of the DHP with a site on the amino-terminal inactivation domain or the DHP binding site at the inner mouth of the channel. Regardless of the mechanism involved, the identical modulation by DHP agonists and antagonists is a distinctive feature of A-type K+ channels in adrenal zona fasciculata cells.

Volume 46, Issue 4, pp. 743-749, 10/01/1994
Copyright © 1994 by American Society for Pharmacology and Experimental Therapeutics

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