INHIBITION BY CARBAMAZEPINE OF VARIOUS ION CHANNELS MEDIATED CATECHOLAMINE SECRETION IN CULTURED BOVINE ADRENAL-MEDULLARY CELLS

The effects of carbamazepine (CBZ) on Na-22(+) influx, Ca-45(2+) influ x, catecholamine secretion and cyclic GMP production were examined in cultured bovine adrenal medullary cells. 1) CBZ (40-120 mu mol/l) inhi bited Na-22(+) influx evoked by carbachol in a concentration-dependent manner. CBZ inhibited carbachol-evoked Ca-45(2+) influx and catechola mine secretion at concentrations similar to those which suppressed Na- 22(+) influx. 2) CBZ (4-120 mu mol/l) inhibited veratridine-induced Na -22(+) influx, Ca-45(2+) influx and catecholamine secretion. 3) CBZ (1 2 or 40-120 mu mol/l) suppressed 56 mmol/l K+-evoked Ca-45(2+) influx and catecholamine secretion, respectively. 4) Combination of CBZ with nitrendipine or omega-agatoxin-IVA produced further inhibition of 56 m mol/l K+- evoked Ca-45(2+) influx and catecholamine secretion, compare d to the effect of CBZ alone, whereas CBZ-plus omega-conotoxin-GVIA di d not produce any further inhibition. 5) CBZ (40 mu mol/l) attenuated the production of cyclic CMP caused by muscarine. These results sugges t that CBZ at therapeutic concentrations (16-48 mu mol/l: 4-12 mu g/ml ) inhibits catecholamine secretion by interfering with nicotinic acety lcholine receptor-associated ion channels, voltage-dependent Na+ chann els and N-type voltage-dependent Ca2+ channels, and may have an antimu scarinic effect in adrenal medullary cells.