Activation of endogenous thromboxane A2 biosynthesis mediates presynaptic inhibition by endothelin-3 of dog stellate ganglionic transmission.

ABSTRACT

Effects of endothelin-3 on ganglionic transmission were investigated in dog cardiac sympathetic ganglia. Positive chronotropic responses to preganglionic stellate stimulation were inhibited by endothelin-3 (0.5-2 micrograms) given directly to the ganglia through the artery. To find possible inhibitory effects of the peptide at presynaptic sites, acetylcholine released from the isolated stellate ganglia was determined. The amount of acetylcholine released during preganglionic stimulation was reduced by exposure to endothelin-3 (10(-9) to 10(-6) M). A similar reduction of acetylcholine release was observed after application of a stable thromboxane A2, a thromboxane A2/prostaglandin H2 receptor agonist, U-46619, and prostaglandin E2 at concentrations from 10(-8) to 10(-4) M, but not by the same concentrations of prostaglandins F2 alpha and I2. The reduction elicited by endothelin-3 was unaffected by a phospholipase C inhibitor, neomycin, or a protein kinase C inhibitor, H-7, but was antagonized by pretreatment with phospholipase A2 inhibitors, dexamethasone or methylprednisolone, and by cyclooxygenase inhibitors, aspirin and indomethacin. In addition, the reduction also 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. Furthermore, endothelin-3 (10(-7) M) stimulated the OKY-046- and indomethacin-sensitive formation of thromboxane A2 in the ganglia. These results indicate that endothelin-3 inhibits the sympathetic ganglionic transmission by reducing acetylcholine release at preganglionic terminals and that this inhibition seems to involve activation of endogenous thromboxane A2 production.