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-act ivated 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 co ncentration 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 mibe fradil was independent of the membrane potential. Mibefradil also reversibl y blocked, with similar potency, unitary I-AC currents recorded in outside- out membrane patches. An analysis of dwell time histograms indicated the pr esence 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, respecti vely, but did not alter the open time constant (tau(o)). Mibefradil also fa iled to reduce the size of the unitary I-AC current. A voltage-gated A-type K+ current was also inhibited by mibefradil at concentrations approximatel y 10-fold higher than those required to block I-AC (IC50 = 4.65 mu M). Thes e results identify mibefradil as a potent inhibitor of ATP-activated K+ cha nnels in adrenal zona fasciculata cells. It appears to function by stabiliz ing 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+ chan nel blocker. In this regard, the block of K+ channels may produce some of t he toxicity associated with mibefradil in cardiovascular pharmacology.