Published online before print August 5, 2002, doi: 10.1161/01.HYP.0000028980.24709.68
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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
Professor of Clinical Pharmacology, Clinical Research Centre, The University of Edinburgh, Western General Hospital, Edinburgh, Scotland, E-mail d.j.webb@ed.ac.uk
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 ETA/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 work2–4 and that of some,4,5 but not all other groups,6,7 with both ETA receptor selective and ETA/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 ETA 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 ETA and ETB 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 ETB receptor.
On this basis, our laboratory has more recently delivered BQ-123 in forearm studies at a dose of 10 nmol/min, with which, if anything, greater effects on local blood flow have been seen.4 This may be explained by the major role of the vascular ETB receptor being to mediate vasodilation,4,11 such that combined ETA/B inhibition may, by blocking ETB mediated effects, attenuate the vasodilation associated with selective ETA receptor antagonism.4 We have also used BQ-788 intra-arterially (at 1 nmol/min) as an ETB selective antagonist, here based on systemic studies showing that 30 nmol/min, but not 3 nmol/min, increases systemic vascular resistance.11
However, a key issue arises for the published body of work using intra-arterial administration of ET receptor antagonists. These investigations have generally used high doses that are likely to be both nonselective and systemically active, conditions that interfere with a clear interpretation of these studies. Cardillo and colleagues gave BQ-123 (at 100 nmol/min) and BQ-788 (at 50 nmol/min) by intra-arterial coadministration to hypertensives and controls to achieve dual ET receptor blockade.6 However, it would now appear that both of these agents were given at systemically active doses. A similar problem of using a systemically active dose of TAK-044 may account for a rather modest effect on vascular tone in healthy subjects in one study7 and the lesser effect of a greater dose of TAK-044 in another.3 By giving systemic doses of the pharmacological probes, responses in the infused forearm may have been influenced directly by changes in systemic vascular resistance or indirectly by the activation of reflex neurohormonal mechanisms.12 In this regard, there must remain some uncertainty about interpretation of work examining the role of endothelin in hypertension and other vascular diseases using drug administration via the brachial artery until these studies are repeated with doses of drugs that are demonstrably confined to a local action.
References
1. Martin P, Ninio D, Krum H. Effect of endothelin blockade on basal and stimulated forearm blood flow in patients with essential hypertension. Hypertension. 2002; 39: 821–824.
2. Haynes WG, Webb DJ. Contribution of endogenous generation of endothelin-1 to basal vascular tone. Lancet. 1994; 344: 852–854.[CrossRef][Medline] [Order article via Infotrieve]
3. Haynes WG, Ferro CE, O’Kane K, Somerville D, Lomax CC, Webb DJ. Systemic endothelin receptor blockade decreases peripheral vascular resistance and blood pressure in man. Circulation. 1996; 93: 1860–1870.
4. Verhaar MC, Strachan FE, Newby DE, Cruden NL, Koomans HA, Rabelink TJ, Webb DJ. Endothelin-A receptor antagonist-mediated vasodilatation is attenuated by inhibition of nitric oxide synthesis and by endothelin-B receptor blockade. Circulation. 1998; 97: 752–756.
5. Berrazueta JR, Bhagat K, Vallance P, MacAllister RJ. Dose-, and time-dependency of the dilator effects of the endothelin antagonist BQ-123, in the human forearm. Br J Clin Pharmacol. 1997; 44: 569–571.[CrossRef][Medline] [Order article via Infotrieve]
6. Cardillo C, Kilcoyne CM, Waclawiw M, Cannon RO3rd, Panza JA. Role of endothelin in the increased vascular tone of patients with essential hypertension. Hypertension. 1999; 33: 753–758.
7. Taddei S, Virdis A, Ghiadoni L, Sudano I, Notari M, Salvetti A. Vasoconstriction to endogenous endothelin-1 is increased in the peripheral circulation of patients with essential hypertension. Circulation. 1999; 100: 1680–1683.
8. Goddard J, Strachan FE, MacCallum H, Cumming AD, Rankin AJ, Webb DJ. Selective ETA endothelin receptor antagonism is as effective in reducing blood pressure and vascular resistance as combined ETA/B receptor antagonism in both healthy volunteers and patients with chronic renal failure. Circulation. 2000; 102: II-417.Abstract.
9. Spratt JCS, Goddard J, Patel N, Strachan FE, Rankin AJ, Webb DJ. Systemic ETA receptor antagonism with BQ-123 blocks ET-1 induced forearm vasoconstriction and decreases peripheral vascular resistance in healthy men. Br J Pharmacol. 2001; 134: 648–54.[CrossRef][Medline] [Order article via Infotrieve]
10. Ishikawa K, Ihara M, Noguchi K, Mase T, Mino N, Saeki T, Fukuroda T, Fukami T, Ozaki S, Nagase T. Biochemical and pharmacological profile of a potent and selective endothelin B-receptor antagonist, BQ-788. Proc Nat Acad Sci U S A. 1994; 91: 4892–4896.
11. Strachan FE, Spratt JC, Wilkinson IB, Johnston N, Gray GA, Webb DJ. Systemic blockade of the endothelin-B receptor increases peripheral vascular resistance in healthy men. Hypertension. 1999; 33: 581–585.
12. Benjamin N, Calver A, Collier J, Robinson B, Vallance P, Webb D. Measuring forearm blood flow and interpreting the responses to drugs and mediators. Hypertension. 1995; 25: 918–923.
Response
Clinical Pharmacology Unit, Departments of Medicine and Epidemiology & Preventive Medicine, Monash University, Alfred Hospital, Melbourne, Australia, E-mail henry.krum@med.monash.edu.au
We thank Doctors Goddard and Webb for their comments regarding intra-arterial infusion of endothelin (ET) antagonists. Goddard and Webb raise a number of relevant issues. They reiterate the importance of using subsystemic doses of vasoactive substances to test hypotheses regarding direct effects on the vasculature. The key issue is how to establish that doses are indeed subsystemic. The usual approach includes careful assessment of systemic blood pressure and heart rate responses and/or measurement of forearm blood flow and vascular resistance in the contralateral limb.1 This is really a general issue of the technique itself and not limited to endothelin blockade as the vasoactive substance.
Specific to endothelin blockade, however, is the issue of selectivity of the receptor antagonist. Goddard and Webb suggest that doses of the ETA-"selective" antagonist BQ-123, assumed to be subsystemic in a number of studies,2,3 may indeed be systemically active4 and also block ETB-mediated vasodilation.5 However, this still does not explain differences in vascular responses to this agent given at the same dose and at the same infusion rate over similar periods of time. We used SB209670 in our study6 specifically because it is nonselective, and we wished to test the impact of blockade of all major ET receptor subtypes on the vasculature, between normal subjects and patients with cardiovascular disease.
References
1. Wilkinson IB, Webb DJ. Venous occlusion plethysmography in cardiovascular research: methodology and clinical applications. Br J Clin Pharmacol. 2001; 52: 631–646.[CrossRef][Medline] [Order article via Infotrieve]
2. Haynes WG, Webb DJ. Contribution of endogenous generation of endothelin-1 to basal vascular tone Lancet. 1994; 344: 852–854.[CrossRef][Medline] [Order article via Infotrieve]
3. Cardillo C, Kilcoyne CM, Waclawiw M, Cannon RO3rd, Panza JA. Role of endothelin in the increased vascular tone of patients with essential hypertension. Hypertension. 1999; 33: 753–758.
4. Spratt JC, Goddard J, Patel N, Strachan FE, Rankin AJ, Webb DJ. Systemic ETA receptor antagonism with BQ-123 blocks ET-1 induced forearm vasoconstriction and decreases peripheral vascular resistance in healthy men. Br J Pharmacol. 2001; 134: 648–654.[CrossRef][Medline] [Order article via Infotrieve]
5. Verhaar MC, Strachan FE, Newby DE, Cruden NL, Koomans HA, Rabelink TJ, Webb DJ. Endothelin-A receptor antagonist-mediated vasodilatation is attenuated by inhibition of nitric oxide synthesis and by endothelin-B receptor blockade. Circulation. 1998; 97: 752–756.
6. Martin P, Ninio D, Krum H. Effect of endothelin blockade on basal and stimulated forearm blood flow in patients with essential hypertension. Hypertension. 2002; 39: 821–824.
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