title: Action of the endothelin receptor (ETA) antagonist BQ-123 on forearm blood flow in young normotensive subjects.
abstract: Endothelin-1 (ET-1) has been proposed to contribute to the regulation of vascular tone in humans. BQ-123, an ET(A) receptor antagonist, has also been reported to increase forearm blood flow (FBF) in vivo; however, the efficacy of BQ-123 as an antagonist of ET-1 has not been evaluated in the forearm. The present study investigated the effects of BQ-123 on changes in FBF in response to ET-1 and noradrenaline (NA; norepinephrine), taking into account the possible influence of vasodilator effects of BQ-123 on responses to vasoconstrictors. Six subjects (age 25-34 years) participated in a double-blind randomized study. FBF was measured by forearm occlusion plethysmography. Drugs were infused intra-arterially into the non-dominant arm (study arm) on four separate occasions; the non-infused arm was used as a control. The effects of BQ-123 (50 nmol/min for 60 min, or 300 nmol/min for 5 min followed by saline for 55 min) were compared with the effects of infusion of sodium nitroprusside (SNP; 12 nmol/min for 60 min) or saline on vasoconstriction induced by ET-1 (10 pmol/min for 7 min) and NA (120 pmol/min for 7 min). Infusion of BQ-123 at either dose did not significantly increase FBF, whereas SNP increased FBF by 134% (P=0.03). ET-1 significantly reduced FBF, and this effect was almost completely inhibited by both doses of BQ-123, but was unaffected by SNP. NA also reduced FBF, and this action was unaffected by BQ-123 or SNP. The data show that BQ-123 is a selective ET-1 antagonist, but do not confirm a major role for ET-1 in influencing resting forearm vascular tone in young normotensive subjects.
authors.affiliation: Clinical Pharmacology, NHLI, Imperial College School of Medicine, St Mary's Hospital, London W2 1NY, UK. r.wimalasundera@ic.ac.uk
authors.forename: R C
authors.initials: RC
authors.lastname: Wimalasundera
authors.forename: S A
authors.initials: SA
authors.lastname: McG Thom
authors.forename: L
authors.initials: L
authors.lastname: Regan
authors.forename: A D
authors.initials: AD
authors.lastname: Hughes
mesh_terms: D000328:Adult; D000959:Antihypertensive Agents / Q000494:pharmacology*; D004311:Double-Blind Method; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D005542:Forearm / Q000098:blood supply*; D006801:Humans; D009599:Nitroprusside; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010991:Plethysmography; D012039:Regional Blood Flow / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010456:Peptides, Cyclic; D014665:Vasodilator Agents; D009599:Nitroprusside; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D009638:Norepinephrine