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(Circulation. 1998;97:752-756.)
© 1998 American Heart Association, Inc.

Clinical Investigation and Reports

Endothelin-A Receptor Antagonist–Mediated Vasodilatation Is Attenuated by Inhibition of Nitric Oxide Synthesis and by Endothelin-B Receptor Blockade

Marianne C. Verhaar, MD; Fiona E. Strachan, BN, RGN; David E. Newby, BSc, MB, MRCP; Nicholas L. Cruden, BSc, MB, ChB; Hein A. Koomans, MD, PhD; Ton J. Rabelink, MD, PhD; ; David J. Webb, MD, FRCP

From the Department of Nephrology and Hypertension (M.C.V., H.A.K., T.J.R.), University Hospital Utrecht, The Netherlands, and the Department of Medicine (F.E.S., D.E.N., N.L.C., D.J.W.), University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, Scotland.

Correspondence to Dr Marianne Verhaar, Department of Nephrology and Hypertension, Room F 03.226, Heidelberglaan 100, 3584 CX Utrecht, University Hospital Utrecht, The Netherlands. E-mail t.rabelink{at}digd.azu.nl

Background—The role of endothelin (ET)-1 in maintenance of basal vascular tone has been demonstrated by local and systemic vasodilatation to endothelin receptor antagonists in humans. Although the constrictor effects mediated by the vascular smooth muscle ET_A receptors are clear, the contribution from endothelial and vascular smooth muscle ET_B receptors remains to be defined. The present study, in human forearm resistance vessels in vivo, was designed to further investigate the physiological function of ET_A and ET_B receptor subtypes in human blood vessels and determine the mechanism underlying the vasodilatation to the ET_A-selective receptor antagonist BQ-123.

Methods and Results—Two studies were performed, each in groups of eight healthy subjects. Brachial artery infusion of BQ-123 caused significant forearm vasodilatation in both studies. This vasodilatation was reduced by 95% (P=.006) with inhibition of the endogenous generation of nitric oxide and by 38% (P<.001) with coinfusion of the ET_B receptor antagonist BQ-788. In contrast, inhibition of prostanoid generation did not affect the response to BQ-123. Infusion of BQ-788 alone produced a 20% reduction in forearm blood flow (P<.001).

Conclusions—Selective ET_A receptor antagonism causes vasodilatation of human forearm resistance vessels in vivo. This response appears to result in major part from an increase in nitric oxide generation. ET_B receptor antagonism either alone or on a background of ET_A antagonism causes local vasoconstriction, indicating that ET_B receptors in blood vessels respond to ET-1 predominantly by causing vasodilatation.

Key Words: endothelin • nitric oxide • flow • receptors • prostaglandins

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				P. A. MacCarthy, R. Grocott-Mason, B. D. Prendergast, and A. M. Shah Contrasting Inotropic Effects of Endogenous Endothelin in the Normal and Failing Human Heart : Studies With an Intracoronary ETA Receptor Antagonist Circulation, January 18, 2000; 101(2): 142 - 147. [Abstract] [Full Text] [PDF]

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				A. Montanari, A. Biggi, N. Carra, E. Fasoli, M. Calzolari, F. Corsini, P. Perinotto, and A. Novarini Endothelin-A Blockade Attenuates Systemic and Renal Hemodynamic Effects of L-NAME in Humans Hypertension, January 1, 2000; 35(1): 518 - 523. [Abstract] [Full Text] [PDF]

				H. Berthold, A. Just, H. R. Kirchheim, and H. Ehmke Interaction Between Nitric Oxide and Endogenous Vasoconstrictors in Control of Renal Blood Flow Hypertension, December 1, 1999; 34(6): 1254 - 1258. [Abstract] [Full Text] [PDF]

				S. Taddei, A. Virdis, L. Ghiadoni, I. Sudano, M. Notari, and A. Salvetti Vasoconstriction to Endogenous Endothelin-1 Is Increased in the Peripheral Circulation of Patients With Essential Hypertension Circulation, October 19, 1999; 100(16): 1680 - 1683. [Abstract] [Full Text] [PDF]

				E. L. Schiffrin Role of Endothelin-1 in Hypertension Hypertension, October 1, 1999; 34(4): 876 - 881. [Abstract] [Full Text] [PDF]

				C. Cardillo, S. S. Nambi, C. M. Kilcoyne, W. K. Choucair, A. Katz, M. J. Quon, and J. A. Panza Insulin Stimulates Both Endothelin and Nitric Oxide Activity in the Human Forearm Circulation, August 24, 1999; 100(8): 820 - 825. [Abstract] [Full Text] [PDF]

				E. Thorin, R. Parent, Z. Ming, and M. Lavallee Contribution of endogenous endothelin to large epicardial coronary artery tone in dogs and humans Am J Physiol Heart Circ Physiol, August 1, 1999; 277(2): H524 - H532. [Abstract] [Full Text] [PDF]

				H. Berthold, K. Munter, A. Just, H. R. Kirchheim, and H. Ehmke Stimulation of the Renin-Angiotensin System by Endothelin Subtype A Receptor Blockade in Conscious Dogs Hypertension, June 1, 1999; 33(6): 1420 - 1424. [Abstract] [Full Text] [PDF]

				M. C. Verhaar, M. L.H. Honing, T. van Dam, M. Zwart, H. A. Koomans, J. J.P. Kastelein, and T. J. Rabelink Nifedipine improves endothelial function in hypercholesterolemia, independently of an effect on blood pressure or plasma lipids Cardiovasc Res, June 1, 1999; 42(3): 752 - 760. [Abstract] [Full Text] [PDF]

				T. Ohuchi, T. Kuwaki, G.-Y. Ling, D. Dewit, K.-H. Ju, M. Onodera, W.-H. Cao, M. Yanagisawa, and M. Kumada Elevation of blood pressure by genetic and pharmacological disruption of the ETB receptor in mice Am J Physiol Regulatory Integrative Comp Physiol, April 1, 1999; 276(4): R1071 - R1077. [Abstract] [Full Text] [PDF]

				X.-Z. Zhang and C. Baylis Endothelin mediates renal vascular memory of a transient rise in perfusion pressure due to NOS inhibition Am J Physiol Renal Physiol, April 1, 1999; 276(4): F629 - F634. [Abstract] [Full Text] [PDF]

				H. Berthold, K. Munter, A. Just, H. R. Kirchheim, and H. Ehmke Contribution of endothelin to renal vascular tone and autoregulation in the conscious dog Am J Physiol Renal Physiol, March 1, 1999; 276(3): F417 - F424. [Abstract] [Full Text] [PDF]

				C. Cardillo, C. M. Kilcoyne, M. Waclawiw, R. O. Cannon III, and J. A. Panza Role of Endothelin in the Increased Vascular Tone of Patients With Essential Hypertension Hypertension, February 1, 1999; 33(2): 753 - 758. [Abstract] [Full Text] [PDF]

				E. L. A. Blezer, K. Nicolay, R. Goldschmeding, G. H. Jansen, H. A. Koomans, T. J. Rabelink, and J. A. Joles Early-Onset But Not Late-Onset Endothelin-A–Receptor Blockade Can Modulate Hypertension, Cerebral Edema, and Proteinuria in Stroke-Prone Hypertensive Rats Hypertension, January 1, 1999; 33(1): 137 - 144. [Abstract] [Full Text] [PDF]

				F. E. Strachan, J. C. Spratt, I. B. Wilkinson, N. R. Johnston, G. A. Gray, and D. J. Webb Systemic Blockade of the Endothelin-B Receptor Increases Peripheral Vascular Resistance in Healthy Men Hypertension, January 1, 1999; 33(1): 581 - 585. [Abstract] [Full Text] [PDF]

				Z. Ming, R. Parent, E. Thorin, and M. Lavallee Endothelin-Dependent Tone Limits Acetylcholine-Induced Dilation of Resistance Coronary Vessels After Blockade of NO Formation in Conscious Dogs Hypertension, November 1, 1998; 32(5): 844 - 848. [Abstract] [Full Text] [PDF]

				T. J Rabelink, E. S.G Stroes, K.P. Bouter, and P. Morrison Endothelin blockers and renal protection: a new strategy to prevent end-organ damage in cardiovascular disease? Cardiovasc Res, September 1, 1998; 39(3): 543 - 549. [Full Text] [PDF]

				W. G. Haynes, C. J. Ferro, D. J. Webb, B. K. Kramer, F. Schweda, G. A.J. Riegger, H. Krum, Y. Lacourciere, and V. Charlon Bosentan in Essential Hypertension N. Engl. J. Med., July 30, 1998; 339(5): 346 - 347. [Full Text]

				F. Bohm, G. Ahlborg, B.-L. Johansson, L.-O. Hansson, and J. Pernow Combined Endothelin Receptor Blockade Evokes Enhanced Vasodilatation in Patients With Atherosclerosis Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 674 - 679. [Abstract] [Full Text] [PDF]