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(Hypertension. 2002;40:e1.)
© 2002 American Heart Association, Inc.

Letters to the Editor

Endothelin Antagonists and Hypertension: A Question of Dose?

Lecturer in Renal Medicine, Clinical Research Centre, The University of Edinburgh

David J. Webb

Professor of Clinical Pharmacology, Clinical Research Centre, The University of Edinburgh, Western General Hospital, Edinburgh, Scotland, E-mail d.j.webb@ed.ac.uk

An extract of the first 250 words of the full text is provided, because this article has no abstract.

To the Editor:

We read with interest the recent report in Hypertension from Martin et al¹ on the effects of intra-arterial administration of the endothelin ET_A/B receptor antagonist, SB 209670, on forearm blood flow in hypertensive subjects and matched controls. Their finding of forearm vasodilation to intra-arterial SB 209670 in healthy controls suggests a role for endothelin-1 (ET-1) in regulation of basal vascular tone and is consistent with our own work^2–4 and that of some,^4,5 but not all other groups,^6,7 with both ET_A receptor selective and ET_A/B receptor antagonists. Also, contrary to some earlier work,^6,7 they find no difference from controls in the in vivo response of the resistance vessels of hypertensive subjects to ET receptor antagonism.

Our early intra-arterial studies were undertaken with the ET_A selective antagonist, BQ-123, at a dose of 100 nmol/min.² We have since undertaken pharmacodynamic and kinetic dose-ranging systemic studies with BQ-123 and find that this dose of BQ-123 has modest systemic effects, more on vascular resistance than blood pressure.^8,9 Maximum plasma concentrations of BQ-123 at 100 nmol/min were 585±158 nmol/L,⁸ and IC₅₀ values for BQ-123 at the ET_A and ET_B receptors in vitro are 9 to 24 nmol/L and 10 to 18 000 nmol/L, respectively, depending on cell type.¹⁰ Hence, when given locally into the forearm (blood flow 50 mL/min) rather than the systemic circulation (5 000 mL/min), this dose of BQ-123 will achieve concentrations (60 000 nmol/L) that may have functionally important inhibitory effects at the ET_B receptor.

On this basis, our laboratory has . . . [Full Text of this Article]

Paul Martin; Henry Krum

Clinical Pharmacology Unit, Departments of Medicine and Epidemiology & Preventive Medicine, Monash University, Alfred Hospital, Melbourne, Australia, E-mail henry.krum@med.monash.edu.au

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