Mibefradil potently blocks ATP-activated K+ channels in adrenal cells

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 (I-AC) expressed by adrenal zona fasciculata cells. I-AC channels were inhibited by mibefradil with an IC50 value of 0.50 mu M, a concentration 2-fold lower than that required to inhibit T-type Ca2+ channels under similar conditions in the same cells. The inhibition of I-AC by mibefradil was independent of the membrane potential. Mibefradil also reversibly blocked, with similar potency, unitary I-AC currents recorded in outside-out membrane patches. An analysis of dwell time histograms indicated the presence of two closed and one open state. Mibefradil (1 mu M) increased the duration of the two closed time constants (tau(c1) and tau(c2)) 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 (tau(o)). Mibefradil also failed to reduce the size of the unitary I-AC current. A voltage-gated A-type K+ current was also inhibited by mibefradil at concentrations approximately 10-fold higher than those required to block I-AC (IC50 = 4.65 mu M). 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.