Venous endothelin receptor function in patients with chronic heart failure

Cardiac preload reduction through venodilatation is beneficial in chronic heart failure. The recent development of endothelin receptor antagonists for possible therapeutic use in heart failure has hastened the need for a clearer understanding of the venoconstrictor actions of endothelin-1 in this disease. Two main subtypes of endothelin receptor, ET(A) and ET(B), exist in human blood vessels. We studied the venoconstrictor effects of endothelin-1 (a non-selective ET(A) and ET(B) agonist) and sarafotoxin S6c (a selective ET(B) agonist) in vivo in patients with chronic heart failure and in age-matched healthy controls. On separate days at least 1 week apart, locally active doses of endothelin-1 or sarafotoxin S6c were infused into a suitable dorsal hand vein for 1 h, and the venous internal diameter was measured using a displacement technique. Venoconstriction in response to endothelin-1 was significantly blunted in heart failure patients compared with controls (26+/-7% and 51+/-6% peak reduction in vein calibre respectively; P=0.013). Venoconstriction to sarafotoxin S6c was similar in heart failure patients and controls (17+/-5% and 17+/-4% peak reduction in vein calibre respectively). Both ET(A) and ET(B) receptors mediate venoconstriction in healthy subjects and in patients with chronic heart failure. Optimal inhibition of the venoconstrictor effects of endothelin-1 in chronic heart failure may therefore require administration of an antagonist with ET(A)- and ET(B)-receptor-blocking properties. Chronic heart failure may be associated with a selective decrease in venous ET(A) receptor sensitivity, but further studies are required to clarify the functional significance of this observation.