PT - JOURNAL ARTICLE AU - Juan Carlos Gomora AU - Judith A. Enyeart AU - John J. Enyeart TI - Mibefradil Potently Blocks ATP-Activated K<sup>+</sup> Channels in Adrenal Cells AID - 10.1124/mol.56.6.1192 DP - 1999 Dec 01 TA - Molecular Pharmacology PG - 1192--1197 VI - 56 IP - 6 4099 - http://molpharm.aspetjournals.org/content/56/6/1192.short 4100 - http://molpharm.aspetjournals.org/content/56/6/1192.full SO - Mol Pharmacol1999 Dec 01; 56 AB - Mibefradil is a novel Ca2+ channel antagonist that preferentially blocks T-type Ca2+ channels in many cells. Using whole-cell and single-channel patch-clamp recording, we found that mibefradil also potently blocked an ATP-activated K+channel (IAC) expressed by adrenal zona fasciculata cells. IAC channels were inhibited by mibefradil with an IC50 value of 0.50 μM, a concentration 2-fold lower than that required to inhibit T-type Ca2+ channels under similar conditions in the same cells. The inhibition of IAC by mibefradil was independent of the membrane potential. Mibefradil also reversibly blocked, with similar potency, unitary IACcurrents recorded in outside-out membrane patches. An analysis of dwell time histograms indicated the presence of two closed and one open state. Mibefradil (1 μM) increased the duration of the two closed time constants (τc1 and τc2) from 2.30 ± 0.18 and 27.9 ± 4.7 ms to 4.32 ± 0.61 and 62.5 ± 13.8 ms, respectively, but did not alter the open time constant (τo). Mibefradil also failed to reduce the size of the unitary IAC current. A voltage-gated A-type K+current was also inhibited by mibefradil at concentrations approximately 10-fold higher than those required to block IAC (IC50 = 4.65 μM). These results identify mibefradil as a potent inhibitor of ATP-activated K+ channels in adrenal zona fasciculata cells. It appears to function by stabilizing closed states of these channels. In contrast to its selective block of T-type Ca2+ channels, mibefradil may be a potent but less-selective K+ channel blocker. In this regard, the block of K+ channels may produce some of the toxicity associated with mibefradil in cardiovascular pharmacology.