Endothelin-1 stimulates sodium-dependent calcium efflux from bovine adrenal chromaffin cells in culture

1. The effect of endothelin (ET)-1 on Ca²⁺ efflux from cultured bovine adrenal chromaffin cells was examined. ET-1 (10^-7 M) significantly increased intracellular free Ca²⁺ level ([Ca²⁺](i)), ⁴⁵Ca²⁺ uptake and catecholamine secretion in the cells. 2. ET-1 stimulated the efflux of ⁴⁵Ca²⁺ from the cells preloaded with ⁴⁵Ca²⁺ in a concentration-dependent manner (10^-9-10^-7 M). This stimulatory effect was inhibited by ET(B) receptor antagonist BQ788, but not by ET(A) receptor antagonist BQ123. Selective ET(B) receptor agonists Suc-[Glu⁹ Ala^11,15]-ET-1 and sarafotoxin S6c (SRTX) also stimulated ⁴⁵Ca²⁺ efflux from the cells. 3. ET-1, Suc-[Glu⁹, Ala^11,15]-ET-1 and SRTX increased the level of cyclic GMP in the adrenal chromaffin cells. ET-1 induced an increase in the nitric oxide (NO) level in the cells. The stimulatory effects by which ET-1 increases NO level and ⁴⁵Ca²⁺ efflux were inhibited by N(G)-monomethyl-L-arginine acetate (L-NMMA), a competitive inhibitor of NO synthase. 4. The ⁴⁵Ca²⁺ efflux stimulated by ET-1 was inhibited by deprivation of extracellular Na⁺, but not by deprivation of Ca²⁺. 5. These results suggest that ET-1 stimulates an extracellular Na⁺-dependent Ca²⁺ efflux through the activation of NO synthase in cultured bovine adrenal chromaffin cells.