Endothelin-3 Inhibits Ganglionic Transmission at Preganglionic Sites Through Activation of Endogenous Thromboxane A2 Production in Dog Cardiac Sympathetic Ganglia

Abstract

The effects of endothelin-3 (ET-3) on ganglionic transmission of dog cardiac sympathetic ganglia and possible mechanisms involved were investigated in vivo and in vitro. Positive chronotropic responses to preganglionic stellate stimulation and those to dimethylphenylpiperazinium as well as McN-A-343 administered to the ganglia were inhibited by ET-3. The amount of acetylcholine released by preganglionic stimulation was reduced dose dependently after exposure to ET-3. The reduction elicited by ET-3 was antagonized by pretreatment with phospholipase A2 inhibitors (dexamethasone and methylprednisolone) and cyclooxygenase inhibitors (aspirin and indomethacin). In addition, the reduction of acetylcholine release was similarly induced by exposure to exogenously applied STA2, a stable thromboxane A2 analogue; U-46619, a TXA2/PGH2 receptor agonist; and prostaglandin E2. Furthermore, the reduction produced by ET-3 was antagonized by pretreatment with a thromboxane A2 synthetase inhibitor (OKY-046) and a specific thromboxane A2 receptor antagonist (S-145), but not by a specific prostaglandin E2 receptor antagonist (SC-19220). These results indicate that ET-3 inhibits the sympathetic ganglionic transmission via reducing acetylcholine release from the presynaptic nerve terminals of ganglia and that this inhibition involves the activation of endogenous thromboxane A2 production.