© 1997 American Heart Association, Inc.
Articles |
Enhanced Endothelin-B-Receptor–Mediated Vasoconstriction of Small Porcine Coronary Arteries in Diet-Induced Hypercholesterolemia
From the Division of Internal Medicine and Cardiovascular Diseases (D.H., V.M., R.S.S., D.R.H. Jr), and the Departments of Anesthesiology and Pharmacology, Mayo Clinic and Mayo Foundation, Rochester, Minn (L.A.S., Z.S.K.).
Correspondence to Amir Lerman, MD, Division of Cardiovascular Diseases, Mayo Clinic, 200 First St SW, Rochester, Minn 55905. E-mail: lerman.amir{at}mayo.edu
Abstract The coronary vasoconstrictor effects of endothelins, mediated by both endothelin ETA and ETB receptors, may be differentially altered in pathophysiological states associated with endothelial dysfunction and elevated endothelin levels. Experimental hypercholesterolemia is associated with coronary endothelial dysfunction and increased circulating endothelin concentrations. These studies were designed to test the hypothesis that experimental hypercholesterolemia is characterized by a differentially altered coronary contractile response to ETA- and ETB-receptor stimulation, in vitro. Pigs were fed either a normal or a high-cholesterol diet for 10 to 13 weeks. Changes in the intraluminal diameter of pressurized small coronary arteries (<481±25 µm in diameter) to cumulative concentrations (10-10 to 10-6 mol/L) of endothelin-1 (ET-1), and sarafotoxin 6c (S6c), a specific ETB-receptor agonist, were measured using a video dimension analyzer. The maximal contraction attained with ET-1 was greater than with S6c in both normal (86±7% versus 47±7%, P=.001) and hypercholesterolemic (77±6% versus 37±7%, P<.001) pigs. At 10-10 mol/L, vessels from hypercholesterolemic pigs manifested greater contraction to both ET-1 (23±6% versus 8±3%, P=.02) and S6c (17±5% versus 4±2%, P=.02). Incubation of arteries from hypercholesterolemic pigs with BQ-788 (ETB-receptor antagonist), but not FR-139317 (ETA-receptor antagonist), altered the contractile response to ET-1 at 10-10 mol/L. Removal of the endothelium abolished the difference in response to S6c between normal and hypercholesterolemic pigs. These studies demonstrate that experimental hypercholesterolemia is characterized by enhanced coronary vasoconstriction to endothelins in vitro, the mechanism of which is mediated mainly through the ETB receptor. Thus, the ETB receptor has a role in regulation of coronary artery tone in both the steady-state and pathophysiological states.
Key Words: endothelin • sarafotoxin • receptors • hypercholesterolemia • pigs • endothelium
This article has been cited by other articles:
 |
|
 |
|
  T. W. Cherng, M. J. Campen, T. L. Knuckles, L. Gonzalez Bosc, and N. L. Kanagy Impairment of coronary endothelial cell ETB receptor function after short-term inhalation exposure to whole diesel emissions Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2009; 297(3): R640 - R647. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Sato, T. Komaru, H. Shioiri, S. Takeda, K. Takahashi, H. Kanatsuka, M. Nakayama, and K. Shirato Hypercholesterolemia Impairs Transduction of Vasodilator Signals Derived From Ischemic Myocardium: Myocardium-Microvessel Cross-Talk Arterioscler Thromb Vasc Biol, November 1, 2004; 24(11): 2034 - 2039. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
M. Rodriguez-Porcel, L. O. Lerman, J. Herrmann, T. Sawamura, C. Napoli, and A. Lerman Hypercholesterolemia and Hypertension Have Synergistic Deleterious Effects on Coronary Endothelial Function Arterioscler Thromb Vasc Biol, May 1, 2003; 23(5): 885 - 891. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Rodriguez-Porcel, L. O Lerman, D. R Holmes Jr., D. Richardson, C. Napoli, and A. Lerman Chronic antioxidant supplementation attenuates nuclear factor-{kappa}B activation and preserves endothelial function in hypercholesterolemic pigs Cardiovasc Res, March 1, 2002; 53(4): 1010 - 1018. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. H. Wilson, R. D. Simari, P. J. M. Best, T. E. Peterson, L. O. Lerman, M. Aviram, K. A. Nath, D. R. Holmes Jr, and A. Lerman Simvastatin Preserves Coronary Endothelial Function in Hypercholesterolemia in the Absence of Lipid Lowering Arterioscler Thromb Vasc Biol, January 1, 2001; 21(1): 122 - 128. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. J. F. Hill, L. C. Katwa, B. R. Wamhoff, and M. Sturek Enhanced EndothelinA Receptor-Mediated Calcium Mobilization and Contraction in Organ Cultured Porcine Coronary Arteries J. Pharmacol. Exp. Ther., November 1, 2000; 295(2): 484 - 491. [Abstract] [Full Text]
|
|
|
|
|
|
P. J. M. Best, L. O. Lerman, J. C. Romero, D. Richardson, D. R. Holmes Jr, and A. Lerman Coronary Endothelial Function Is Preserved With Chronic Endothelin Receptor Antagonism in Experimental Hypercholesterolemia In Vitro Arterioscler Thromb Vasc Biol, November 1, 1999; 19(11): 2769 - 2775. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Hasdai, M. F. Nielsen, R. A. Rizza, D. R. Holmes Jr, D. M. Richardson, P. Cohen, and A. Lerman Attenuated In Vitro Coronary Arteriolar Vasorelaxation to Insulin-like Growth Factor I in Experimental Hypercholesterolemia Hypertension, July 1, 1999; 34(1): 89 - 95. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. J. M. Best, C. J. McKenna, D. Hasdai, D. R. Holmes Jr, and A. Lerman Chronic Endothelin Receptor Antagonism Preserves Coronary Endothelial Function in Experimental Hypercholesterolemia Circulation, April 6, 1999; 99(13): 1747 - 1752. [Abstract] [Full Text] [PDF]
|
|