Comparison of selective ET(A) and ET(B) receptor antagonists in patients with chronic heart failure.
BACKGROUND
The vasoconstrictor action of endothelin-1 (ET-1) is mediated through ET(A) and ET(B) receptor subtypes on vascular smooth muscle. ET(B) receptors are also present on the vascular endothelium where they mediate vasodilation. Animal studies suggest that the ET(B) receptor also acts as a clearance receptor for endothelin.


OBJECTIVE
To investigate the effects of a selective ET(A) and a selective ET(B) receptor antagonist alone and in combination on haemodynamics and circulating concentrations of ET-1 in patients with chronic heart failure.


RESULTS
Infusion of BQ-123 (n=10), a selective ET(A) receptor antagonist, led to systemic vasodilation and did not change plasma ET-1 concentrations (1.38+/-0.82 to 1.38+/-0.91 fmol/ml, ns). Infusion of BQ-788 (n=8) led to systemic vasoconstriction with a rise in plasma ET-1 (1.84+/-1.06 to 2.73+/-0.99 fmol/ml, p<0.01). The addition of BQ-123 to BQ-788 led to systemic and pulmonary vasodilation with no further increase in plasma ET-1 concentrations (2.80+/-1.14 to 2.90+/-1.20 fmol/ml, ns).


CONCLUSIONS
The rise in plasma ET-1 concentrations in response to selective blockade of ET(B) receptors and the associated adverse haemodynamic effects suggest that ET(B) receptors have a role in the clearance of ET-1 in man and that their blockade may not be advantageous for patients with heart failure.
Cowburn
Peter J
PJ
Wessex Cardiothoracic Centre, Southampton General Hospital, Mailpoint 46, Tremona Road, Southampton, SO16 6YD, UK. pjcowburn@hotmail.com
Cleland
John G F
JG
McDonagh
Theresa A
TA
McArthur
John D
JD
Dargie
Henry J
HJ
Morton
James J
JJ
D000368:Aged; D004359:Drug Therapy, Combination; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood* / Q000187:drug effects; D005260:Female; D006333:Heart Failure / Q000097:blood* / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000494:pharmacology; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology
D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; C086539:BQ 788; C072247:cyclo(Trp-Asp-Pro-Val-Leu)