This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kinlay, S. Articles by Ganz, P. Search for Related Content PubMed PubMed Citation Articles by Kinlay, S. Articles by Ganz, P. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Coronary Artery Disease Hazardous Substances DB NITROGLYCERIN Related Collections Pathophysiology Coronary circulation Endothelium/vascular type/nitric oxide Other Vascular biology

(Circulation. 2001;104:1114.)
© 2001 American Heart Association, Inc.

Clinical Investigation and Reports

Role of Endothelin-1 in the Active Constriction of Human Atherosclerotic Coronary Arteries

Scott Kinlay, MBBS, PhD; Dominik Behrendt, MD; Marco Wainstein, MD; John Beltrame, BMBS; James C. Fang, MD; Mark A. Creager, MD; Andrew P. Selwyn, MD; Peter Ganz, MD

From the Cardiovascular Division, Brigham and Women’s Hospital, Boston, Mass.

Correspondence to Scott Kinlay, MBBS, PhD, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115. E-mail skinlay{at}rics.bwh.harvard.edu

Background—— Atherosclerotic coronary arteries are prone to constriction but the underlying causes are incompletely understood. We tested the hypothesis that endothelin-1 (ET-1), a potent vasoconstrictor, contributes to the heightened tone of atherosclerotic human coronary arteries.

Methods and Results—— In 8 patients with coronary artery disease (CAD) and 8 patients with angiographically smooth coronary arteries (normal), we infused BQ-123, an antagonist of the ET_A receptor, into a major coronary artery (infused artery) at 40 nmol/min for 60 minutes. The infused artery in the CAD patients contained a >50% stenosis. Using quantitative angiography, we compared the dilation of the infused artery with another, noninfused coronary artery. To estimate the magnitude of the contribution of ET-1 to coronary tone, we compared the dilation to BQ-123 with that elicited by intracoronary nitroglycerin (200 µg). BQ-123 induced significant dilation in the normal arteries (7.3% at 60 minutes, P<0.001 versus noninfused arteries) and a greater dilation in the CAD arteries (16.3% at 60 minutes, P<0.001 versus infused normal arteries). The dilation at stenoses was particularly pronounced (21.6% at 60 minutes, P<0.001 versus infused CAD arteries). Compared with the dilation from nitroglycerin, ET-1 contributed to 39% of the coronary tone in normal arteries, 74% of tone in CAD arteries, and 106% of tone at stenoses (P<0.01).

Conclusions—— ET-1 accounts for nearly all the resting tone in atherosclerotic coronary arteries, especially at stenoses. Inhibitors of ET-1, by relieving constriction, may significantly lessen the hemodynamic significance of coronary stenoses and thereby reduce myocardial ischemia.

Key Words: endothelin • endothelium • vasoconstriction • atherosclerosis

This article has been cited by other articles:

				S. N. Saleh, A. P. Albert, and W. A. Large Activation of native TRPC1/C5/C6 channels by endothelin-1 is mediated by both PIP3 and PIP2 in rabbit coronary artery myocytes J. Physiol., November 15, 2009; 587(22): 5361 - 5375. [Abstract] [Full Text] [PDF]

				K. Stangl and V. Stangl The ubiquitin proteasome pathway and endothelial (dys)function Cardiovasc Res, October 13, 2009; (2009) cvp315v2. [Abstract] [Full Text] [PDF]

				E. Larose, D. Behrendt, S. Kinlay, A. P. Selwyn, P. Ganz, and J. C. Fang Endothelin-1 Is a Key Mediator of Coronary Vasoconstriction in Patients With Transplant Coronary Arteriosclerosis Circ Heart Fail, September 1, 2009; 2(5): 409 - 416. [Abstract] [Full Text] [PDF]

				P Wexberg, W Sperker, N G Morgenthaler, H Heinzl, C Adlbrecht, C Plass, H D Glogar, I M Lang, and T Neunteufl Inhomogeneous vasomotor effects of moderate selective and non-selective endothelin-receptor blockade in stable coronary artery disease Heart, August 1, 2009; 95(15): 1258 - 1264. [Abstract] [Full Text] [PDF]

				F. Bohm and J. Pernow The importance of endothelin-1 for vascular dysfunction in cardiovascular disease Cardiovasc Res, October 1, 2007; 76(1): 8 - 18. [Abstract] [Full Text] [PDF]

				C. M. Peppiatt-Wildman, A. P. Albert, S. N. Saleh, and W. A. Large Endothelin-1 activates a Ca2+-permeable cation channel with TRPC3 and TRPC7 properties in rabbit coronary artery myocytes J. Physiol., May 1, 2007; 580(3): 755 - 764. [Abstract] [Full Text] [PDF]

				J. P.J. Halcox, K. R.A. Nour, G. Zalos, and A. A. Quyyumi Endogenous Endothelin in Human Coronary Vascular Function: Differential Contribution of Endothelin Receptor Types A and B Hypertension, May 1, 2007; 49(5): 1134 - 1141. [Abstract] [Full Text] [PDF]

				R. Jaumdally, C. Varma, R. J. Macfadyen, and G. Y.H. Lip Coronary sinus blood sampling: an insight into local cardiac pathophysiology and treatment? Eur. Heart J., April 2, 2007; 28(8): 929 - 940. [Abstract] [Full Text] [PDF]

				A. Lerman, D. R. Holmes, J. Herrmann, and B. J. Gersh Microcirculatory dysfunction in ST-elevation myocardial infarction: cause, consequence, or both? Eur. Heart J., April 1, 2007; 28(7): 788 - 797. [Abstract] [Full Text] [PDF]

				J. E. Deanfield, J. P. Halcox, and T. J. Rabelink Endothelial Function and Dysfunction: Testing and Clinical Relevance Circulation, March 13, 2007; 115(10): 1285 - 1295. [Full Text] [PDF]

				C. Kusmic, G. Lazzerini, F. Coceani, R. Barsacchi, A. L'Abbate, and G. Sambuceti Paradoxical coronary microcirculatory constriction during ischemia: a synergic function for nitric oxide and endothelin Am J Physiol Heart Circ Physiol, October 1, 2006; 291(4): H1814 - H1821. [Abstract] [Full Text] [PDF]

				B. Battistini, N. Berthiaume, N. F. Kelland, D. J. Webb, and D. E. Kohan Profile of Past and Current Clinical Trials Involving Endothelin Receptor Antagonists: The Novel "-Sentan" Class of Drug. Experimental Biology and Medicine, June 1, 2006; 231(6): 653 - 695. [Abstract] [Full Text] [PDF]

				W. L Hall, K. Vafeiadou, J. Hallund, S. Bugel, C. Koebnick, M. Reimann, M. Ferrari, F. Branca, D. Talbot, T. Dadd, et al. Soy-isoflavone-enriched foods and inflammatory biomarkers of cardiovascular disease risk in postmenopausal women: interactions with genotype and equol production Am. J. Clinical Nutrition, December 1, 2005; 82(6): 1260 - 1268. [Abstract] [Full Text] [PDF]

				I. A. Khan Role of Endothelin-1 in Acute Myocardial Infarction Chest, May 1, 2005; 127(5): 1474 - 1476. [Full Text] [PDF]

				G. Sambuceti, M. Marzilli, A. Mari, C. Marini, M. Schluter, R. Testa, M. Papini, P. Marraccini, G. Ciriello, P. Marzullo, et al. Coronary microcirculatory vasoconstriction is heterogeneously distributed in acutely ischemic myocardium Am J Physiol Heart Circ Physiol, May 1, 2005; 288(5): H2298 - H2305. [Abstract] [Full Text] [PDF]

				A. Just, A. J. M. Olson, J. R. Falck, and W. J. Arendshorst NO and NO-independent mechanisms mediate ETB receptor buffering of ET-1-induced renal vasoconstriction in the rat Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2005; 288(5): R1168 - R1177. [Abstract] [Full Text] [PDF]

				A. Lerman and A. M. Zeiher Endothelial Function: Cardiac Events Circulation, January 25, 2005; 111(3): 363 - 368. [Full Text] [PDF]

				J. Davignon and P. Ganz Role of Endothelial Dysfunction in Atherosclerosis Circulation, June 15, 2004; 109(23_suppl_1): III-27 - III-32. [Abstract] [Full Text]

				A. Nohria, L. Garrett, W. Johnson, S. Kinlay, P. Ganz, and M. A. Creager Endothelin-1 and Vascular Tone in Subjects With Atherogenic Risk Factors Hypertension, July 1, 2003; 42(1): 43 - 48. [Abstract] [Full Text] [PDF]

				Z. He, C. Rask-Madsen, and G.L. King Mechanisms of cardiovascular complications in diabetes and potential new pharmacological therapies Eur. Heart J. Suppl., January 1, 2003; 5(suppl_B): B51 - B57. [Abstract] [PDF]

				A. D. Seftel Challenges in Oral Therapy for Erectile Dysfunction J Androl, November 1, 2002; 23(6): 729 - 736. [Full Text] [PDF]

				U. Lockowandt and A. Franco-Cereceda Is there a role for endothelin-blockade early after coronary artery bypass grafting? Ann. Thorac. Surg., September 1, 2002; 74(3): 727 - 732. [Abstract] [Full Text] [PDF]

				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]

				U. Lockowandt, S. Bjessmo, T. Ivert, and A. Franco-Cereceda Plasma levels and vascular effects of endothelin and big endothelin in patients with stable and unstable angina pectoris undergoing coronary bypass grafting Eur. J. Cardiothorac. Surg., February 1, 2002; 21(2): 218 - 223. [Abstract] [Full Text] [PDF]

				J. P.J. Halcox, K. R.A. Nour, G. Zalos, and A. A. Quyyumi Coronary Vasodilation and Improvement in Endothelial Dysfunction With Endothelin ETA Receptor Blockade Circ. Res., November 23, 2001; 89(11): 969 - 976. [Abstract] [Full Text] [PDF]

				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]

				C. Ferri, G. Properzi, G. Tomassoni, A. Santucci, G. Desideri, A. E. Giuliani, R. C. Starling, N. B. Ratliff, D. J. Cook, P. McCarthy, et al. Patterns of Myocardial Endothelin-1 Expression and Outcome After Cardiac Transplantation Circulation, April 16, 2002; 105(15): 1768 - 1771. [Abstract] [Full Text] [PDF]