BIG ET-1 INFUSION IN MAN CAUSES RENAL ET-1 RELEASE, RENAL AND SPLANCHNIC VASOCONSTRICTION, AND INCREASED MEAN ARTERIAL BLOOD-PRESSURE

Objective: The aim was to study the vascular effects of big endothelin-1 (big ET-1) infusion and its possible conversion to ET-1. Methods: Six healthy subjects were given an intravenous infusion of big ET-1 in a dose of 8 pmol.kg(-1).min(-1) for 20 min. Blood samples were taken before, during, and up to 3 h after the infusion from arterial, hepatic, and renal vein catheters for the determination of splanchnic and renal blood flows, as well as ET-1-like immunoreactivity (ET-1-LI) from these vascular beds. Results: Intravenous infusion of big ET-1 was followed by a doubling of arterial ET-1-LI from 4.17(SEM 0.39) to 8.42(0.49) pmol.litre(-1) (p < 0.001) and a significant increase in the renal release of ET-1-LI from 1.50(0.18) to 8.68(0.64) pmol.min(-1) (p < 0.001) but no splanchnic release. Big ET-1 infusion also caused a decrease in heart rate from 57(4) to 45(3) beats.min(-1) (p < 0.001) and an increase in mean arterial pressure from 86(1.3) to 106(3.2) mm Hg (p < 0.001), which lasted for at least 2 h. Renal blood flow fell from 1.38(0.06) to 0.83(0.04) litre.min(-1) (p < 0.001) while splanchnic blood flow fell from 1.34(0.11) to 0.83(0.05) litre.min(-1) (p < 0.001). Conclusions: Big ET-1 infusion causes a drop in heart rate, an increase in mean arterial pressure and decreases in splanchnic and renal blood flows. Arterial plasma ET-1 levels doubled and big ET-1 infusion also induced a significantly increased renal, but not splanchnic, release of ET-1-LI, suggesting a unique renal handling of circulating big ET-1. When the results of the infusion of big ET-1 are compared with our previous experiments using ET-1 infusion, more marked haemodynamic changes (as reflected in the increase in mean arterial pressure, the drop in heart rate, and the duration of renal vasoconstriction) are seen despite lower arterial plasma ET-1-LI levels.