Whether endothelin-1 or -3 is capable of inducing histamine release from the peritoneal mast cells of BALB/c mice was investigated in vitro and compared to the release induced by compound 48/80. In contrast to the mouse bone marrow-derived mast cells, which originated from the same strain and have been reported upon previously, the (both crude and purified) peritoneal mast cells potently secreted histamine in response to either endothelin-1 or endothelin-3 in a concentration-dependent fashion. Even at a concentration as low as 10 nM, endothelin-1 induced a histamine release of more than 50% from the peritoneal mast cells. Cyclo(D-Asp-Pro-D-Val-Leu-D-Trp) (BQ-123), an endothelin ET_A receptor antagonist, markedly suppressed not only the histamine release induced by endothelin-1 but also that due to endothelin-3 at a similarly low concentration range. Treatment with islet-activating protein (IAP) for 3 h, an inactivator of guanosine triphosphate (GTP) (G_i)-protein, markedly reduced the histamine release induced by endothelin-1. Neomycin at 0.1 and 1 mM or ethylenediaminetetraacetic acid (EDTA) at 0.1 mM in the absence of Ca²⁺, neither of which affected the histamine release induced by endothelin-1, substantially reduced histamine release caused by compound 48/80. On the other hand, treatment with O-O′-bis(2-aminophenyl)ethylenegly-col-N, N,N′,N′-tetraacetic acid, tetraacetoxymethyl ester (BAPTA-AM), an intracellular calcium chelating agent, completely inhibited the release induced by both endothelin-1 and compound 48/80. These results indicate that endothelin-1 is one of the most potent histamine releasers in mouse peritoneal mast cells discovered so far. Endothelin-1 acts by inducing the activation of G_i-protein, which, in turn, increases the cytosolic Ca²⁺ concentration derived from the intracellular calcium store and finally leads to the release of histamine, via endothelin ET_A receptor stimulation. It is likely that the histamine release induced by endothelin-1 is induced by mechanisms partly different from that of3compound 48/80.