Mibefradil potently blocks ATP-activated K(+) channels in adrenal cells.
Mibefradil is a novel Ca(2+) channel antagonist that preferentially blocks T-type Ca(2+) 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 IC(50) value of 0.50 microM, a concentration 2-fold lower than that required to inhibit T-type Ca(2+) 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 microM) 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) (IC(50) = 4.65 microM). 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 Ca(2+) 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.
Gomora
J C
JC
Department of Pharmacology, The Ohio State University College of Medicine and Public Health, Columbus, Ohio, USA.
Enyeart
J A
JA
Enyeart
J J
JJ
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002417:Cattle; D004594:Electrophysiology; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D020748:Mibefradil / Q000494:pharmacology*; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000378:metabolism; D018043:Receptors, Corticotropin / Q000378:metabolism; D013997:Time Factors; D015383:Zona Fasciculata / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
D002121:Calcium Channel Blockers; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D018043:Receptors, Corticotropin; D020748:Mibefradil; D000255:Adenosine Triphosphate; D002118:Calcium