METABOLISM OF BIG ENDOTHELIN-1-(1-38) AND ENDOTHELIN-1-(22-38) IN THEHUMAN CIRCULATION IN RELATION TO PRODUCTION OF ENDOTHELIN-1-(1-21)

Healthy male volunteers received intravenous infusions of Big endothel in (ET)-1 (1-38) or Big ET-1 (22-38). Blood samples were drawn from ca theters in the brachial and pulmonary arteries and the hepatic, renal, jugular and deep forearm veins. The in vivo half-lives of circulating plasma Big ET-1 (1-38) were 6.61+/-0.3 min for the initial phase and 23 +/- 1.4 min for the late phase. The corresponding half-lives of Big ET-1 (22-38) were considerably shorter, being 0.9 +/- 0.03 min (P<0.0 1) and 3.1 +/- 0.4 min (P<0.01), respectively. This was concordant wit h the efficient regional clearance of Big ET-1 (22-38), which was most prominent in the forearm muscle (51 +/- 3%), liver (44 +/- 5%) and ki dney (43 +/- 3 %) and less pronounced in the lungs (14 +/- 2%) and bra in (22 +/- 5%). Significant fractional extraction of Big ET-1 (1-38) w as only found for the liver (30 +/- 2%) and kidney (44 +/- 3 %). Durin g the infusion of Big ET-1 (1-38) a positive veno-arterial gradient of ET-1-LI was noted only for the kidney, indicating production of ET-1. Tn conclusion, whereas Big ET-I (22-38)is eliminated in skeletal musc le, splanchnic, renal, pulmonary and cerebral vascular beds, Big ET-1 (1-38) is extracted mainly in the renal and splanchnic vasculature. Fu rthermore, plasma half-life of Big ET-1 (1-38) is much longer than tha t of both ET-1 and Big ET-1 (22-38) in man. Thus, for investigation of the secretory activity of the ET-1-system measurements of Big ET-1 (1 -38) levels may be a better approach.