Divalent cations effectively replace Ca²⁺ and support bradykinin induced noradrenaline release

Bradykinin (BK), a nonapeptide acting at the B₂-type BK-receptor, and depolarization with high KCl (50 mM), induce catecholamine secretion in pheochromocytoma cells (PC-12). The mechanism underlying the BK-induced release, which is absolutely Ca²⁺-dependent, is not yet understood. Alkaline metals, barium (Ba²⁺), strontium (Sr²⁺) and other metal cations, manganese (Mn²⁺) or lanthanum (La³⁺), support BK-induced [³H]noradrenaline ([³H]NA) release. The extent of supporting transmitter release is dependent upon the specificity of the extracellular cation, with rank order potency of: Ba²⁺ > Sr²⁺ > Ca²⁺ > Mn²⁺La³⁺. The same rank order potency was observed for supporting both BK- and K⁺-induced release. [³H]NA release in the presence of Ba²⁺ or Sr²⁺ was much greater than in the presence of Ca²⁺, and unlike with Ca²⁺ was not saturable at the highest concentration measured. La³⁺ and Mn²⁺ were significantly less effective than Ca²⁺ at supporting release. These results strongly suggest that extracellular Ca²⁺ entry is essential for release, and that BK mediates release via a receptor-operated Ca²⁺ channel.