VASCULAR EFFECTS, FORMATION, CLEARANCE AND RELEASE OF ENDOTHELIN PEPTIDES IN THE PIG

The formation, release, clearance and vascular effects of endothelin (ET)-like immunoreactivity (-LI) was studied in the pig in vivo. Intravenous infusion of ET-1, 2 and 3 (20 pmol/kg/min for 20 min) increased vascular resistance in the kidney, spleen and skeletal muscle. The most pronounced effects were evoked by ET-1 which caused increases in renal, splenic and skeletal muscle vascular resistance of 554, 528 and 38%, respectively, and a threshold response was observed at 80 pmo1/1 ET-LI in arterial plasma. During the infusion a large portion of arterial plasma, ET-LI was cleared over the kidney, spleen and skeletal muscle, whereby the most pronounced clearance was observed for ET-1 (73-93%). The ET-1 precursor Big-ET (1-39) given in a similar dose produced only a slight increase in renal vascular resistance (by 20%) and was cleared only over the kidney and not over the spleen or skeletal muscle. Using an ET-1 specific antiserum it was found that plasma ET-1 levels increased 11-fold during the infusion of Big-ET, indicating formation of ET-1 from Big-ET. The half-lives of circulating ET-1, 2 and 3 were 1.3-2.1 min and of Big-ET 8.9 min. Induction of asphyxia for 2 min increased the overflow of ET-LI from the spleen, suggesting local release, and caused splenic vasoconstriction. During i.v. administration of endotoxin for 4 h, arterial plasma ET-LI increased 7-fold and renal and splenic vasoconstrictor responses developed that correlated significantly with the arterial plasma ET-LI. Furthermore, a local release of ET-LI in the spleen was observed during endotoxin administration. Chromatographic characterizatio of the ET-LI in plasma during endotoxin administration revealed presence of ET-1 and Big-ET. It is concluded that there exists specificity both concerning the vasoconstrictor effects and removal from the circulation of ET peptides, both mechanisms being most prominent for ET-1 in the kidney. Furthermore ET-1 seems to be formed from circulating Big-ET and release of ET-LI can be detected during situations like asphyxia and sepsis.