Regional extraction of endothelins and conversion of big endothelin to endothelin-1 in the pig

Abstract

Endothelin-like immunoreactivity (ET-LI), mean arterial blood pressure (MABP) and vascular resistance in the spleen, kidney and femoral vascular bed were measured during intravenous infusions (20 pmol.kg-1.min) of endothelin-2 (ET-2), endothelin-3 (ET-3), big endothelin-1 (big ET) and sarafotoxin 6b in the pig. All peptides (especially endothelin-2 and sarafotoxin 6b) caused vasoconstrictor effects in the kidney. Endothelin-2, endothelin-3 and sarafotoxin 6b also evoked significant increases in splenic and femoral vascular resistance. The relative vasoconstrictor response to endothelin-2 was larger in the kidney and spleen than in the femoral vascular bed whereas the opposite was observed for endothelin-3. A high degree of plasma clearance for endothelin-like immunoreactivity was observed. Thus, for ET-2 and ET-3 about 70% of arterial endothelin-like immunoreactivity was removed over the kidney while over the spleen and femoral vascular bed an extraction of 50% for plasma endothelin-2 and 30-40% for endothelin-3 was observed. Big endothelin-1 was only extracted by 34% over the kidney and not at all in the splenic or femoral vascular bed. The metabolic plasma half-lifes of endothelin-2 and endothelin-3 in vivo were in the same range, 1-2 minutes, whereas the half-life of big endothelin-1 was 9 minutes. HPLC-characterization of the plasma endothelin-like immunoreactivity during and after big endothelin-1 infusion as well as measurements using a specific endothelin-1 antiserum revealed formation of endothelin-1 from circulating big endothelin-1 in vivo but not in plasma in vitro. It is concluded that there exists specificity concerning the vasoconstrictor effects and the removal of endothelin-peptides from the circulation, both mechanisms being most prominent in the kidney. Big endothelin-1 has a much longer metabolic half-life, less regional clearance and poor vasoconstrictor activity compared with endothelin-1. Furthermore, endothelin-1 is formed from circulating big endothelin-1 probably by an endothelin-converting enzyme.