Endothelin receptor antagonism in patients with chronic heart failure.

ABSTRACT

OBJECTIVE: The relative importance of ETA and ETB receptors in mediating the constrictor effects of endogenous endothelin-1 in patients with chronic heart failure is not known. The primary purpose of this study was to compare the acute effects of selective ETA and ETB receptor antagonists in vivo in healthy subjects and patients with chronic heart failure. Our secondary aim was to examine more closely the effect of chronic heart failure on endothelin biosynthesis. METHODS: We studied the effects of BQ-123 (a selective ETA antagonist) and BQ-788 (a selective ETB antagonist) in ten healthy subjects and ten patients with chronic heart failure. Locally active doses of each antagonist were infused into the non-dominant brachial artery for 90 min on separate days at least 1 week apart. Changes in forearm blood flow were measured by venous occlusion plethysmography. Venous blood samples were obtained prior to antagonist infusion for assay of total endothelin, big endothelin-1 and C-terminal fragment immunoreactivity. RESULTS: BQ-123 (100 nmol/min) increased blood flow by 54+/-10% (P<0.001) and 30+/-5% (P<0.001) in controls and heart failure patients, respectively. BQ-788 (1 nmol/min) reduced blood flow by 15+/-5% (P=0. 036) and 9+/-4% (P=0.001) in controls and heart failure patients, respectively. Total endothelin immunoreactivity was non significantly greater in heart failure patients than controls (6. 8+/-1.4 vs. 4.6+/-0.5 pM; P=0.13). Big endothelin-1 (2.6+/-0.4 vs. 1. 7+/-0.1 pM; P=0.04) and C-terminal fragment immunoreactivity (2. 1+/-0.3 vs. 0.6+/-0.1 pM; P<0.0001) were each significantly greater in heart failure patients than controls. CONCLUSIONS: Selective ETA receptor antagonism caused vasodilatation in the peripheral circulation of healthy subjects and patients with chronic heart failure while selective ETB receptor antagonism caused vasoconstriction in each group. ETB receptor antagonism may therefore cause potentially deleterious vasoconstriction in chronic heart failure. Chronic heart failure is associated with a significant increase in plasma big endothelin-1 and C-terminal fragment immunoreactivity.