Pharmacological characterization of receptor-mediated Ca2+ entry in endothelin-1-induced catecholamine release from cultured bovine adrenal chromaffin cells

To clarify the mechanism for the endothelin-l (ET-1)-induced release of cat echolamines from the adrenal grand, we examined the effects of removal of e xtracellular Ca2+, blockers of L-. N-, P- and Q-types of voltage-operated C a2+ channels (VOCC) such as nifedipme (L-type), omega-conotoxin GVIA (N-typ e), omega-agatoxin IVA (P-type) and omega-conotoxin MVIIC (Q-type) and bloc kers of voltage-independent Ca2+ entry channel such as SK&F 96365 and LOE 9 08 on release of catecholamines, the cytosolic free Ca2+ concentration ([Ca 2+](i)), and Ca-45(2+) uptake in cultured bovine adrenal chromaffin cells. ET-I but not ET-3 induced increases in release of catecholamines, [Ca2+](i) , and Ca-45(2+) uptake. The responses to ET-I were abolished by the antagon ist for ETA receptors, BQ-123, but not by the antagonist for ETB receptors, BQ-788, and they were abolished by removal of extracellular Ca2+. The incr eases were only partially inhibited (to about 65% of control) by nifedipine but unaffected by any of the omega-toxins. The nifedipine-resistant increa se was inhibited by SK&F 96365 (to about 40%) and abolished by LOE 908 alon e. These results indicate that ET-I augments the release of catecholamines from adrenal chromaffin cells through ETA receptors, by activating two type s of Ca2+ entry channels in addition to L-type VOCC: one (nonselective cati on channel-1, NSCC-1) is sensitive to LOE 908 but resistant to SK&F 96365. whereas the other (NSCC-2) is sensitive to both LOE 908 and SK&F 96365.