Big Endothelin-1-induced Sudden Death is Inhibited by Phosphoramidon in Mice

The lethal activity of big endothelin-1 (bET-1) was examined in mice and compared with endothelin-1 (ET-1). Like ET-1, intravenous administration of bET-1 produced sudden death with an approximate LD50 value at 21.0 nmol/kg, higher than that of ET-1 (3.8 nmol/kg). At doses above the respective LD90 value, the latency to death was much longer in bET-1-treated mice with sustained elevation of plasma immunoreactive ET-1 (IR-ET-1). A metalloproteinase inhibitor, phosphoramidon, although failing to inhibit sudden death induced by ET-1, suppressed bET-1-induced lethality and elevation of plasma IR-ET-1 probably due to an inhibition of the enzymatic conversion of bET-1 to ET-1.