Evidence for release of endothelin-1 in pigs and humans.
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 pM. ET-1-LI in fetal umbilical arterial plasma was very high (15 pM before and 94 pM after establishment of breathing) compared with about 2 pM 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.
Lundberg
J M
JM
Department of Pharmacology, Karolinska Institute, Stockholm, Sweden.
Ahlborg
G
G
Hemsén
A
A
Nisell
H
H
Lunell
N O
NO
Pernow
J
J
Rudehill
A
A
Weitzberg
E
E
D000818:Animals; D016232:Endothelins / Q000378:metabolism* / Q000493:pharmacokinetics; D005260:Female; D005333:Fetus / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D011247:Pregnancy; D012771:Shock, Hemorrhagic / Q000503:physiopathology; D012772:Shock, Septic / Q000378:metabolism; D013045:Species Specificity; D013552:Swine / Q000378:metabolism*; D014661:Vasoconstriction / Q000187:drug effects
D016232:Endothelins