Enhanced vasoconstrictor effect of big endothelin-1 in patients with atherosclerosis: relation to conversion to endothelin-1

The enhanced production of endothelin-1 (ET-1) in atherosclerotic arteries may be related to increased activity of the endothelin converting enzyme (ECE) which converts big ET-1 to ET-1. The purpose of the present study was to investigate whether the vasoconstrictor activity of big ET-1 is altered as a result of increased conversion to ET-1 in patients with atherosclerosis. Big ET-1 was infused into the brachial artery of nine patients with atherosclerosis and nine healthy controls. Forearm blood flow (FBF) was measured with venous occlusion plethysmography. Big ET-1 (15 and 50 pmol/min) evoked more pronounced reduction in FBF in the patients than in the controls (P<0.01). The low dose big ET-1 elevated local venous plasma ET-1 (from 2.8±0.3 to 9.0±1.6 pmol/l; P<0.01) and the net formation of ET-1 (from −6.6±8.6 to 50.5±16.0 fmol/min; P<0.01) in the patients but not in the controls. Furthermore, histological examination revealed ECE immunoreactivity in the fibrous cap of atherosclerotic plaques in addition to the endothelium and smooth muscle cells of radial arteries. In conclusion, administration of big ET-1 results in enhanced vasoconstriction and increased formation of ET-1 in patients with atherosclerosis as compared to healthy controls which may be due to increased activity of ECE.