(Circulation. 1995;92:3312-3317.)
© 1995 American Heart Association, Inc.
Articles |
Endothelin at Pathophysiological Concentrations Mediates Coronary Vasoconstriction via the Endothelin-A Receptor
From the Cardiorenal Research Laboratory, Division of Cardiovascular Diseases and Internal Medicine, Department of Internal Medicine and Physiology, Mayo Clinic/Foundation, Rochester, Minn.
Correspondence to Amir Lerman, MD, Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, 200 First St, SW, Rochester, MN 55905.
Background Endothelin-1 (ET-1) is an endothelium-derived vasoconstrictor peptide. Controversy persists regarding the predominant ET receptor that mediates coronary vasoconstriction at pathophysiological concentrations. The aim of the present study was to test the hypothesis that ET mediates local coronary vasoconstriction via the ET-A receptor at low concentrations of exogenous ET-1 designed to mimic pathophysiological states compared with pharmacological concentrations.
Methods and Results ET-1 (group 1, n=5) or sarafotoxin, a specific ET-B receptor agonist (group 3, n=6) (each at 2 ng/kg per minute), was infused into the left circumflex coronary artery in the anesthetized dog. In group 2 dogs (n=5), the same dose of ET-1 was infused with 4 µg/kg per minute of the specific ET-A receptor antagonist FR-139317. In group 4 (n=5), the same dose of sarafotoxin was infused with 50 µg/kg per minute of the specific inhibitor of nitric oxide formation, NG-monomethyl-L-arginine (L-NMMA). No difference in hemodynamics, coronary blood flow (CBF), coronary vascular resistance (CVR), or coronary artery diameter (CAD) was observed at baseline between the groups. In group 1, intracoronary ET-1 significantly decreased CBF and CAD in association with an increase in CVR. The percentage decrease in CBF and CAD in the group that received ET-1 and the ET-A receptor antagonist (group 2) was significantly less than that in the group that received ET-1 alone (group 1) (-12±3% versus -48±6% [P<.001] and -4.6±0.8 versus 1.0±0.3 [P<.05], respectively). The administration of the ET-A receptor antagonist (group 2) abolished the ET-mediated increase in CVR (7±5% versus 105±21%, P<.005). There was no significant effect on CBF, CVR, or CAD in the group receiving sarafotoxin alone (group 3). The administration of L-NMMA and sarafotoxin (group 4) resulted in a significant percentage decrease in CBF compared with the group that received sarafotoxin alone (-28±7% versus -8±2% [P<.05]).
Conclusions The present study demonstrates that low concentrations of exogenous ET-1, which may mimic pathophysiological concentrations, result in coronary vasoconstriction mediated predominantly via the ET-A receptor because such vasoconstriction is significantly attenuated by blockade with FR-139317. The ET-B receptor may have a dual vasoconstrictive and vasodilatory effect.
Key Words: endothelin • coronary • receptors
This article has been cited by other articles:
 |
|
 |
|
  D. L. Lee, B. R. Wamhoff, L. C. Katwa, H. K. Reddy, D. J. Voelker, J. L. Dixon, and M. Sturek Increased Endothelin-Induced Ca2+ Signaling, Tyrosine Phosphorylation, and Coronary Artery Disease in Diabetic Dyslipidemic Swine Are Prevented by Atorvastatin J. Pharmacol. Exp. Ther., July 1, 2003; 306(1): 132 - 140. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T.-M. Lee, T.-F. Chou, and C.-H. Tsai Differential Role of KATP Channels Activated by Conjugated Estrogens in the Regulation of Myocardial and Coronary Protective Effects Circulation, January 7, 2003; 107(1): 49 - 54. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Kinnunen, J. Piuhola, H. Ruskoaho, and I. Szokodi AM reverses pressor response to ET-1 independently of NO in rat coronary circulation Am J Physiol Heart Circ Physiol, September 1, 2001; 281(3): H1178 - H1183. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. Gumina, J. Moore, P. Schelling, N. Beier, and G. J. Gross Na+/H+ exchange inhibition prevents endothelial dysfunction after I/R injury Am J Physiol Heart Circ Physiol, September 1, 2001; 281(3): H1260 - H1266. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z S Kyriakides, D T Kremastinos, E Bofilis, D Tousoulis, A Antoniadis, and D J Webb Endogenous endothelin maintains coronary artery tone by endothelin type A receptor stimulation in patients undergoing coronary arteriography Heart, August 1, 2000; 84(2): 176 - 182. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Kjekshus, O. A. Smiseth, R. Klinge, E. Oie, M. E. Hystad, and H. Attramadal Regulation of ET: pulmonary release of ET contributes to increased plasma ET levels and vasoconstriction in CHF Am J Physiol Heart Circ Physiol, April 1, 2000; 278(4): H1299 - H1310. [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]
|
|
|
|
 |
|
 M Mansaray, P.R Belcher, I Vergroesen, Z.M Wright, J.W Hynd, A.J Drake-Holland, and M.I.M Noble Downstream resistance effects of intracoronary thrombosis in the stenosed canine coronary artery Cardiovasc Res, April 1, 1999; 42(1): 193 - 200. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Zellner, A. A. Protter, E. Ko, M. R. Pothireddy, T. DeMarco, S. J. Hutchison, T. M. Chou, K. Chatterjee, and K. Sudhir Coronary vasodilator effects of BNP: mechanisms of action in coronary conductance and resistance arteries Am J Physiol Heart Circ Physiol, March 1, 1999; 276(3): H1049 - H1057. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Geny, F. Piquard, J. Lonsdorfer, and P. Haberey Endothelin and heart transplantation Cardiovasc Res, September 1, 1998; 39(3): 556 - 562. [Full Text] [PDF]
|
|
|
|
|
|
D. Hasdai, D. R. Holmes Jr., D. M. Richardson, U. Izhar, and A. Lerman Insulin and IGF-I attenuate the coronary vasoconstrictor effects of endothelin-1 but not of sarafotoxin 6c Cardiovasc Res, September 1, 1998; 39(3): 644 - 650. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Brunner and L. H. Opie Role of Endothelin-A Receptors in Ischemic Contracture and Reperfusion Injury Circulation, February 3, 1998; 97(4): 391 - 398. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Hasdai, P. J.M. Best, C. R. Cannan, V. Mathew, R. S. Schwartz, D. R. Holmes Jr, and A. Lerman Acute Endothelin-Receptor Inhibition Does Not Attenuate Acetylcholine-Induced Coronary Vasoconstriction in Experimental Hypercholesterolemia Arterioscler. Thromb. Vasc. Biol., January 1, 1998; 18(1): 108 - 113. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Sudhir, E. Ko, C. Zellner, H. E. Wong, S. J. Hutchison, T. M. Chou, and K. Chatterjee Physiological Concentrations of Estradiol Attenuate Endothelin 1–Induced Coronary Vasoconstriction In Vivo Circulation, November 18, 1997; 96(10): 3626 - 3632. [Abstract] [Full Text]
|
|
|
|
|
|
D. Hasdai, V. Mathew, R. S. Schwartz, L. A. Smith, D. R. Holmes Jr, Z. S. Katusic, and A. Lerman Enhanced Endothelin-B-Receptor–Mediated Vasoconstriction of Small Porcine Coronary Arteries in Diet-Induced Hypercholesterolemia Arterioscler. Thromb. Vasc. Biol., November 1, 1997; 17(11): 2737 - 2743. [Abstract] [Full Text]
|
|
|
|
|
|
V. Mathew, C. R. Cannan, V. M. Miller, D. A. Barber, D. Hasdai, R. S. Schwartz, D. R. Holmes Jr, and A. Lerman Enhanced Endothelin-Mediated Coronary Vasoconstriction and Attenuated Basal Nitric Oxide Activity in Experimental Hypercholesterolemia Circulation, September 16, 1997; 96(6): 1930 - 1936. [Abstract] [Full Text]
|
|
|
|
|
|
D. Hasdai, D. R. Holmes, K. N. Garratt, W. D. Edwards, and A. Lerman Mechanical Pressure and Stretch Release Endothelin-1 From Human Atherosclerotic Coronary Arteries In Vivo Circulation, January 21, 1997; 95(2): 357 - 362. [Abstract] [Full Text]
|
|
|
|
|
|
C. R. Cannan, J. C. Burnett Jr, and A. Lerman Enhanced Coronary Vasoconstriction to Endothelin-BReceptor Activation in Experimental Congestive Heart Failure Circulation, February 15, 1996; 93(4): 646 - 651. [Abstract] [Full Text]
|
|