Evidence for Release of Endothelin-1 in Pigs and Humans

Abstract

The release and pharmacokinetics of endothelin-1 (ET-1) in plasma were studied in pigs and humans in vivo. Between 50–90% of plasma ET-1-like immunoreactivity (LI) was cleared by the pig and human kidney, splanchnic circulation, and skeletal muscle. The precursor big ET-1 was only cleared to a moderate extent (34%) by the kidney with progressive formation of ET-1-LI in the pig. The half-lives of circulating ET-1-LI and big ET-1-LI were about 1 and 10 min, respectively. The threshold vasoconstrictor effects for plasma ET-1-LI in the splanchnic and renal circulation in humans were around 30 p M. ET-1-LI in fetal umbilical arterial plasma was very high (15 p M before and 94 p M after establishment of breathing) compared with about 2 p M in maternal plasma. Bacterial endotoxin or sepsis increased ET-1-LI in plasma more than fivefold in both pigs and humans reaching levels close to threshold vasoconstriction. However, hemorrhagic shock or hypotension did not alter plasma ET-1-LI. It is concluded that ET-1 has a short half-life with very high regional plasma clearance, which limits detection of overflow into the systemic circulation. However, release of ET-1 reaching vasoconstrictor levels seems to occur both upon special physiological circulatory changes in the newborn and in septic shock.