Vasodilator effects of the endothelin ET receptor selective antagonist BMS-193884 in healthy men.
OBJECTIVE
A number of endothelin receptor antagonists (ERAs) are currently in clinical development as potential therapies in states characterized by vasoconstriction, such as systemic hypertension. We investigated the haemodynamic effects of locally and systemically active doses of BMS-193884, an endothelin A (ET(A)) receptor selective ERA, and its influence on vasoconstriction to endothelin-1 (ET-1) in healthy men.


METHODS
In three separate randomized, placebo-controlled studies, the forearm blood flow (FBF) response to intra-arterial (i.a.) infusion of ET-1 (5 pmol min(-1)) was assessed during i.a. co-infusion of BMS-193884 (5 and 50 nmol min(-1)), and at 12 and at 24 h after oral administration of BMS-193884 (50, 100 and 200 mg at 12 h; and 200 mg at 24 h). Data were examined by repeated-measures analysis of variance (anova) with treatment and subject as factors.


RESULTS
ET-1 caused significant forearm vasoconstriction, attenuated after oral dosing with BMS-193884 (200 mg) at 12 (P < 0.01) and 24 h (P < 0.0001). BMS-193884 (50 nmol min(-1), i.a.) caused local vasodilatation (25 +/- 11%) when infused alone (P = 0.02) and abolished forearm vasoconstriction to ET-1 (P < 0.0001 vs. ET-1 alone). Orally, BMS-193884 (200 mg) caused a reduction in total systemic vascular resistance at 12 (-14 +/- 9%, P = 0.03) and 24 h (-12 +/- 7%, P < 0.0001). There was no rise in plasma ET-1 levels.


CONCLUSIONS
BMS-193884 causes local and systemic vasodilatation and attenuation of local vasoconstriction to ET-1. The absence of a rise in plasma endothelin levels suggests BMS-193884 is selective for the ET(A) receptor. This form of pharmacodynamic modelling may be useful in the development of ERAs in cardiovascular disease.
Dhaun
Neeraj
N
Clinical Pharmacology Unit & Research Centre, University of Edinburgh, Edinburgh, UK. bean.dhaun@ed.ac.uk
Strachan
Fiona E
FE
Newby
David E
DE
Johnston
Neil R
NR
Ford
Neville F
NF
Hammett
Janis L
JL
Palmisano
Maria
M
Webb
David J
DJ
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D004311:Double-Blind Method; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007261:Infusions, Intra-Arterial; D008297:Male; D008875:Middle Aged; D010080:Oxazoles / Q000097:blood / Q000494:pharmacology*; D044022:Receptor, Endothelin A / Q000502:physiology; D012039:Regional Blood Flow / Q000187:drug effects; D013449:Sulfonamides / Q000097:blood / Q000494:pharmacology*; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
C412823:BMS 193884; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D010080:Oxazoles; D044022:Receptor, Endothelin A; D013449:Sulfonamides; D014665:Vasodilator Agents