915-77 Big ET-1-lnfusion in Man Causes Only Renal ET-1-Release but Potent and Long-lasting Systemic, Pulmonary, Renal and Splanchnic Vasoconstriction

Abstract

Plasma endothelin-1, ET-1, and the precursor, big ET-1, are demonstrable in healthy man and increase during e.g. myocardial infarction (Miyauchi et al 1989). To study the vascular effects of big ET-1 infusion, and its possible conversion of ET-1, healthy subjects received big ET-1 in doses of 4–8 pmol.kg -1 .min -1 intravenously for 20 minutes. Blood samples were taken from systemic arterial and pulmonary arterial as well as jugular, deep forearm, hepatic and renal vein catheters for determination of cardiac output, CO, splanchnic (ESBF) and renal (ERBF) blood flows (indicators: cardiogreen and PAH) forearm blood flow (FBF, pletysmographyl. and big ET-1 and ET-1 like immuno-reactivity, (ET-1-Li). Big ET-1 infusion caused a decrease in heart rate, HR, from 57 ± 4 to 45 ± 3 beats.min-1 (p < 0.001) and increase of mean arterial pressure, MAP, from 86 ± 1.3 to 106 ± 3.2 mmHg (p < 0.001). CO fell by 22 ± 5% (p < 0.01). Pulmonary, splanchnic and renal oxygen uptakes were unchanged indicating that big ET-1 does not influence oxygen consumption. The arterial-jugular venous oxygen difference was unchanged indicating unchanged cerebral blood flow. FBF was unchanged. ERBF and ESBF fell by approximately 40% (both p < 0.001). Only splanchnic and renal tissues extract big ET-1 with fractional extractions of 23 ± 4 and 45 ± 4%. Intravenous infusion of big ET-1 increased arterial ET-1-Li from 4 to 8 pmol.I-1 (p < 0.001) and renal release of ET-1-Li from 1.50 ± 0.18 to 8.68 ± 0.64 pmol.min-1 (p < 0.001). Big ET-1 infusion causes falls in HR and CO, increase in MAP and decreases in splanchnic and renal blood flows. Uptakes of big ET-1 were only noted in the renal and splanchnic regions with two-fold higher values in the kidneys, p < 0.005. Only the kidney showed increased release of ET-1-Li suggesting a unique renal capacity to synthesize and release big ET-1. Compared to ET-l infusion (Weitzberg et al 1991) big ET-l infusion causes, despite lower arterial plasma ET-1-Li levels, more marked haemodynamic effects as reflected in drops in HR and CO and more marked increase in MAP with more pronounced and long-lasting renal vasoconstriction. In addition big-ET-1 had no effect on cerebral or skeletal muscle blood flows while ET-1 caused dilatations in these regions.