Systemic ETA receptor antagonism with BQ-123 blocks ET-1 induced forearm vasoconstriction and decreases peripheral vascular resistance in healthy men.
1. The effect on systemic haemodynamics of BQ-123, a selective endothelin A (ETA) receptor antagonist, was investigated in healthy men by giving, on separate occasions, ascending intravenous doses of 100, 300, 1000 and 3000 nmol min(-1) BQ-123, each for 15 min, in a randomized, placebo-controlled, double-blind study. The response of forearm blood flow to brachial artery infusion of endothelin-1 (ET-1; 5 pmol min(-1) for 90 min) was also studied using bilateral forearm plethysmography, after systemic pre-treatment, on separate occasions, with one of two doses of BQ-123 (300 and 1000 nmol min(-1) for 15 min) or placebo. 2. Systemic BQ-123 dose-dependently decreased systemic vascular resistance (P<0.01 for all doses vs placebo) and mean arterial pressure (P<0.05 for 300 nmol min(-1) and P<0.01 for 1000 and 3000 nmol min(-1)) during the 60 min following infusion. There were concurrent increases in heart rate and cardiac index. BQ-123, when infused systemically for 15 min, appeared to reach a maximum effect at 1000 nmol min(-1). 3. Intra-brachial ET-1 infusion, after pre-treatment with placebo, caused a slow onset progressive forearm vasoconstriction without systemic effects. This vasoconstriction was attenuated by pre-treatment with BQ-123 at 300 nmol min(-1) and abolished by BQ-123 at 1000 nmol min(-1) (P<0.01 vs placebo). 4. These effects occurred at concentrations of BQ-123 in the plasma (510+/-64 nmol l(-1)) that were ETA receptor selective, and were not accompanied by an increase in plasma ET-1 that would have indicated ETB receptor blockade. 5. We conclude that ETA-mediated vascular tone contributes to the maintenance of basal systemic vascular resistance and blood pressure in healthy men.
Spratt
J C
JC
Clinical Pharmacology Unit & Research Centre, Department of Medical Sciences, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU.
Goddard
J
J
Patel
N
N
Strachan
F E
FE
Rankin
A J
AJ
Webb
D J
DJ
D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D000959:Antihypertensive Agents / Q000494:pharmacology*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D005542:Forearm / Q000502:physiology; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D010456:Peptides, Cyclic / Q000494:pharmacology*; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000502:physiology; D014655:Vascular Resistance / Q000187:drug effects* / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology
D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010456:Peptides, Cyclic; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; C072247:cyclo(Trp-Asp-Pro-Val-Leu)