Direct comparison of selective endothelin A and non-selective endothelin A/B receptor blockade in chronic heart failure.
OBJECTIVE
To investigate the potential differential effects of selective endothelin (ET) A and dual ET-A/B receptor blockade in patients with chronic heart failure.


METHODS
Nine patients with chronic heart failure (New York Heart Association class II-III) each received intravenous infusions of BQ-123 alone (selective ET-A blockade) and combined BQ-123 and BQ-788 (dual ET-A/B blockade) in a randomised, placebo controlled, three way crossover study.


RESULTS
Selective ET-A blockade increased cardiac output (maximum mean (SEM) 33 (12)%, p < 0.001) and reduced mean arterial pressure (maximum -13 (4)%, p < 0.001) and systemic vascular resistance (maximum -26 (8)%, p < 0.001), without changing heart rate (p = 0.38). Dual ET-A/B blockade significantly reduced the changes in all these haemodynamic variables compared with selective ET-A blockade (p < 0.05). Selective ET-A blockade reduced pulmonary artery pressure (maximum 25 (7)%, p = 0.01) and pulmonary vascular resistance (maximum 72 (39)%, p < 0.001). However, there was no difference between these effects and those seen with dual ET-A/B blockade. Unlike selective ET-A blockade, dual ET-A/B blockade increased plasma ET-1 concentrations (by 47 (4)% with low dose and 61 (8)% with high dose, both p < 0.05).


CONCLUSIONS
While there appeared to be similar reductions in pulmonary pressures with selective ET-A and dual ET-A/B blockade, selective ET-A blockade caused greater systemic vasodilatation and did not affect ET-1 clearance. In conclusion, there are significant haemodynamic differences between selective ET-A and dual ET-A/B blockade, which may determine responses in individual patients.
Leslie
S J
SJ
Department of Medical Sciences, The University of Edinburgh, Western General Hospital, Edinburgh, UK.
Spratt
J C S
JC
McKee
S P
SP
Strachan
F E
FE
Newby
D E
DE
Northridge
D B
DB
Denvir
M A
MA
Webb
D J
DJ
D000328:Adult; D000368:Aged; D000959:Antihypertensive Agents / Q000008:administration & dosage*; D002302:Cardiac Output / Q000502:physiology; D002303:Cardiac Output, Low / Q000188:drug therapy* / Q000503:physiopathology; D018592:Cross-Over Studies; D004359:Drug Therapy, Combination; D065130:Endothelin A Receptor Antagonists; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood; D005260:Female; D006339:Heart Rate / Q000502:physiology; D006439:Hemodynamics / Q000502:physiology; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000008:administration & dosage*; D010456:Peptides, Cyclic / Q000008:administration & dosage*; D010880:Piperidines / Q000008:administration & dosage*; D016896:Treatment Outcome; D016276:Ventricular Function / Q000502:physiology
D000959:Antihypertensive Agents; D065130:Endothelin A Receptor Antagonists; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; C086539:BQ 788; C072247:cyclo(Trp-Asp-Pro-Val-Leu)