(Circulation. 1995;92:2426-2431.)
© 1995 American Heart Association, Inc.
Articles |
Endothelin in Coronary Endothelial Dysfunction and Early Atherosclerosis in Humans
From the Division of Cardiovascular Diseases and Internal Medicine, 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.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background The endothelium modulates vascular tone through release of vasodilating substances, such as endothelium-derived relaxing factors, and vasoconstricting substances, such as endothelin. Endothelin concentrations are elevated in humans with atherosclerosis and in hypercholesterolemic pigs. Furthermore, the endothelium-dependent vasodilator acetylcholine increases endothelin in hypercholesterolemia in association with coronary vasoconstriction. The present study was designed to test the hypotheses that coronary endothelial dysfunction in humans is characterized by enhanced coronary and circulating endothelin and that the vasoconstriction associated with acetylcholine results in further release of coronary endothelin.
Methods and Results Coronary and circulating endothelin concentrations were measured at baseline and during intracoronary acetylcholine administration in 20 patients undergoing diagnostic coronary angiography. Patients were divided into two groups on the basis of their response to intracoronary acetylcholine. Group 1 (n=7) demonstrated a normal vasodilatory response, but group 2 (n=13) demonstrated coronary vasoconstriction. Baseline coronary and circulating endothelin concentrations (as determined by coronary sinus and femoral artery measurements, respectively) were higher in patients who responded to acetylcholine with coronary vasoconstriction (group 2) than in group 1 patients (coronary sinus, 15.9±1.0 pg/mL versus 7.1±1.0 pg/mL; femoral, 14.1±0.9 pg/mL versus 6.8±1.0 pg/mL, respectively; P<.01). In response to intracoronary acetylcholine, a further increase in coronary endothelin was observed only in group 2; this increase correlated with changes in coronary artery diameter.
Conclusions This study demonstrates that endothelin immunoreactivity is enhanced in the coronary and systemic circulation in humans with coronary endothelial dysfunction. Moreover, acetylcholine further increased coronary endothelin concentration in patients with coronary endothelial dysfunction and was associated with coronary vasoconstriction. These observations strongly support a role for endothelin as an early participant in and marker for coronary endothelial dysfunction in humans.
Key Words: endothelium • endothelin • acetylcholine • guanosine
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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The endothelium modulates vascular tone through release of vasodilating and vasoconstricting substances. Endothelium-derived relaxing factors (EDRF) produce smooth muscle cell relaxation by stimulation of cGMP. Endothelin-1 (ET-1), which is produced from a 39–amino acid precursor from big ET-1 through a proteolytic processing,1 produces potent systemic, renal, and coronary vasoconstriction at pharmacological and pathophysiological concentrations by binding to specific receptors on the vascular smooth muscle.1 2 3 Endothelin is present in normal plasma, and its circulating and tissue concentrations are elevated in cardiovascular disease associated with endothelial dysfunction4 and coronary spasm.5 In addition to its vasoconstrictive properties, endothelin has mitogenic properties in vitro, suggesting that it has a role as a growth factor.6 Recent reports from our laboratory demonstrated elevated plasma endothelin concentrations in humans with atherosclerosis.7 Specific staining of ET-1–like immunoreactivity of human atherosclerotic aorta demonstrated that endothelin was present in the cytoplasm of both vascular smooth muscle and endothelial cells. These studies strongly support a role for endothelin as a marker for and/or participant in advanced atherosclerosis in humans.
Early coronary atherosclerosis in animal models and humans is characterized by an endothelial dysfunction. This is manifested by a coronary vasoconstrictive response to the endothelium-dependent vasodilator acetylcholine in the absence of gross morphological findings of atherosclerosis.8 9 10 This abnormality may be due to reduced EDRF release or activity. Alternatively, the vasoconstrictive response could be mediated by enhanced release of endothelin, recognizing that this peptide produces potent coronary vasoconstriction and can cause myocardial ischemia in experimental animals.10 11 12
In a recent study, we demonstrated that hypercholesterolemia induced by a 2% cholesterol diet in pigs elevates plasma endothelin concentration and enhances coronary artery tissue endothelin immunoreactivity. The endothelium-dependent vasodilator acetylcholine further increased plasma endothelin in hypercholesterolemia in association with coronary vasoconstriction.13 Thus, endothelin may play a significant role as a modulator of coronary vascular reactivity in the earlier stages of human atherosclerosis and endothelial dysfunction. The present study was designed to test the hypothesis that early atherosclerosis in association with coronary endothelial dysfunction in humans is characterized by enhanced concentrations of coronary and circulating endothelin. We further hypothesized that acetylcholine-mediated coronary vasoconstriction is associated with increased release of endothelin. To address our hypotheses, coronary and circulating endothelin concentrations were measured in patients with minimal coronary artery disease as determined by coronary arteriography. Studies were repeated during intracoronary acetylcholine infusion. Coronary cGMP was also assessed in two groups of patients to assess the activity of the endogenous EDRF system.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Patient Population
This investigation was performed at Mayo Clinic with approval of the Institutional Review Board. Informed consent was obtained from all subjects. The study groups consisted of 20 patients undergoing diagnostic coronary angiography. Patients with heart failure and a left ventricular ejection fraction less than 55%, unstable or rest angina, history of myocardial infarction or coronary angioplasty, use of a radiographic contrast agent within 24 hours of entry into the study, left ventricular hypertrophy, or significant endocrinal, hepatic, or renal disorders were excluded from the study.
Patients were brought to the cardiac catheterization laboratory in a fasting state after all cardiovascular medications had been discontinued for at least 48 hours. Diagnostic coronary angiography was performed via the percutaneous femoral approach without prior administration of nitrates or calcium blockers. The coronary angiogram was reviewed, and patients with a left-dominant circulation were excluded from the study. The coronary artery for the injection of acetylcholine was determined by the presence of less than 50% stenosis of the luminal diameter in the left anterior descending coronary artery without significant stenosis (more than 70%) in another coronary artery. In patients who met the angiographic criteria for the study, a 2.2F Tracker coronary-infusion catheter (SciMed Life System) was advanced through a 0.014-in guiding catheter into the proximal left anterior descending coronary artery. A Goodale-Lubin catheter was introduced percutaneously into the coronary sinus under fluoroscopic guidance via the right femoral vein or right internal jugular vein. Serial 3-minute intracoronary infusions of vasoactive agents were administered in the following sequence: control 1 (5% dextrose in water) followed by graded concentrations of acetylcholine, 10-6 to 10-4 mol (to achieve estimated final blood concentrations in the coronary bed of 10-8, 10-7, and 10-6 mol). Final coronary blood concentrations of acetylcholine have been estimated based on the assumption that blood flow in the left anterior descending coronary artery was 80 mL/min. The infusion was terminated either when a significant vessel vasoconstriction occurred or when the largest dose (10-4 mol) was reached. Infusions were performed with a Harvard pump to enable infusion rates under 1% of estimated coronary blood flow.
At baseline and at the end of each infusion dose, blood samples were obtained from the coronary sinus and femoral artery, and coronary arteriography was performed with 6 mL of a nonionic contrast medium, with the same projection angles that best visualized the left anterior descending coronary artery. Last, 100 µg IC of nitroglycerin was administered into the left anterior descending coronary artery. Throughout each infusion, heart rate, systemic arterial pressure, and ECG were monitored continuously.
In the first 6 patients, the coronary sinus catheter was placed before the diagnostic angiogram was taken, and blood samples were obtained before and after the diagnostic angiogram to evaluate the effect of time and contrast on coronary sinus endothelin concentrations.
Quantitative measurements of the coronary arteries were obtained with electronic caliper measurements from cineangiographic images and were verified using a computer-based image analysis system14 by an independent investigator not aware of the endothelin levels. Each left anterior descending coronary artery was divided into proximal, middle, and distal segments. For each segment, the measurements were performed in the region where the greatest change had occurred during the acetylcholine infusion. An angiographically smooth segment of the proximal, middle, and distal left anterior descending coronary arteries, free of any overlapping branch vessels, was identified in each patient and served as the reference diameter for calculation of diameter stenosis. End-diastolic cine frames that best showed the segment were selected, and calibration of the video and cine images was done, identifying the diameter of the guide catheter. A manual edge-detection program was used to determine the arterial diameter. Segment diameters were determined at baseline and after both acetylcholine and nitroglycerin administration. Left ventricular ejection fraction was measured by cardiac ventriculography or echocardiography.
Radioimmunoassay
Plasma endothelin was determined by the
ET-1,2[125I] assay system from Amersham, as previously
described by our laboratory.13 Blood was drawn into tubes
containing chilled potassium EDTA and immediately placed on ice until
it was centrifuged at 4°C. Plasma was separated and frozen at
-20°C until assay. Before the radioimmunoassay, plasma was acidified
with 0.5% trifluoroacetic acid (TFA). C8 Bond Elut cartridges were
washed with 4 mL of methanol and 4 mL of water to extract the plasma.
After the plasma was applied, cartridges were washed with 2 mL of
normal saline and 6 mL of water. Endothelin was eluted from the
cartridges with 2 mL of 90% methanol in 1% TFA, then dried and
reconstituted for the radioimmunoassay. Recovery of the extraction
procedure was 81% as determined by addition of synthetic ET to plasma,
and interassay and intra-assay variations were 9% and 5%,
respectively. The minimal level of detection was 0.5 pg per tube. The
cross-reactivity of ET-2, ET-3, and proendothelin in this assay was
<5%, <3%, and <37%, respectively. Plasma cGMP was measured by
specific radioimmunoassay technique as previously
described.15 16 Abnormal coronary response to
acetylcholine was defined as a decrease of 20% or more in
coronary artery diameter during peak acetylcholine
administration (acetylcholine, 10-4 mol).
Data Analysis
All results are given as mean±SEM.
Statistical analysis
was performed by repeated measures ANOVA and by Student's t
test for paired/unpaired observation. A value of P<.05 was
accepted as significant.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Effect of Acetylcholine on Coronary Endothelin
Patients were divided into two groups on the basis of their response to intracoronary acetylcholine. Group 1 (n=7) demonstrated a normal response to acetylcholine, characterized by coronary vasodilation. Group 2 (n=13) included patients who demonstrated coronary vasoconstriction in response to intracoronary acetylcholine. The demographic and clinical characteristics of the two groups are outlined in the Table
. There was no distinction between the two groups
in their clinical characteristics, and the two groups were referred for
comparable reasons for diagnostic coronary
angiography. There was no significant difference in the extent of
coronary atherosclerosis, as determined by
quantitative coronary angiography, between the two groups
(group 1, 28±8% versus group 2, 25±10%) or in the left
ventricular ejection fraction (group 1, 69±3 versus group
2, 66±5). Baseline coronary and circulating endothelin
concentrations were higher in the patients who responded to
acetylcholine with coronary vasoconstriction (group 2)
than in the patients who responded to acetylcholine with
coronary vasodilation (group 1) (coronary sinus,
15.9±1.0 pg/mL versus 7.1±1.0 pg/mL; femoral, 14.1±0.9
pg/mL versus 6.8±1.0 pg/mL, respectively; P<.01)
(Fig 1). In response to intracoronary
acetylcholine, a further increase in coronary endothelin
concentrations was observed only in patients in group 2 (from 15.9±1.0
pg/mL to 23.9±1.2 pg/mL, P<.01) (Fig 2)
without a significant change in circulating endothelin concentrations
(from 14.1±0.9 pg/mL to 16.1±1.0 pg/mL).
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No change in coronary and circulating endothelin concentrations was observed in patients in group 1. The increase in coronary sinus endothelin in group 2 patients resulted in a significant endothelin gradient (group 1, 0.1±0.8 pg/mL versus group 2, 6.3±1.5 pg/mL, P<.05) across the coronary bed.
There was no change in coronary sinus (group 1, 7.1±1.1 pg/mL to 7.4±1.2 pg/mL; group 2, 15.9±1.0 pg/mL to 16.0±1.2 pg/mL) or circulating femoral artery endothelin concentrations before and after the diagnostic coronary angiogram. There also was no significant difference between men and women in coronary and circulating endothelin concentrations in response to intracoronary acetylcholine.
In contrast to endothelin levels, baseline
coronary cGMP
concentrations were higher in group 1 patients than in group 2 patients
(coronary sinus, 1.71±0.2 pmol/mL versus 0.5±0.1 pmol/mL,
P<.01). In response to intracoronary
acetylcholine, a further and significant increase in coronary
cGMP was observed only in the group 1 patients. There was no change in
coronary cGMP concentrations in the group 2 patients (Fig 2
).
Although the increase in coronary sinus cGMP in response to
intracoronary acetylcholine in group 1 patients was
significantly higher than in group 2 patients (cGMP, 1.2±0.1 pmol/mL
versus -0.2±0.05 pmol/mL; P<.05), there was no
difference
in the increase in coronary sinus cGMP in response to
intracoronary nitroglycerin between the
groups (Fig 3).
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There was a significant correlation
(r=.9,
P<.01) between peak coronary endothelin
concentrations during the acetylcholine infusion and the peak changes
in coronary artery diameter (Fig 4).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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This study demonstrates that circulating endothelin immunoreactivity is enhanced in the coronary and systemic circulation in humans with altered coronary endothelial function and early atherosclerosis. The endothelium-dependent vasodilator acetylcholine further increased coronary endothelin concentration in patients with coronary endothelial dysfunction and was associated with coronary vasoconstriction. Furthermore, this study demonstrates that coronary cGMP, the second messenger for EDRF activity, is decreased in humans with coronary endothelial dysfunction. Thus, our results show an imbalance between EDRF and endothelin in coronary endothelial dysfunction.
We previously reported the elevation of circulating endothelin in humans with advanced atherosclerosis in association with its presence in atherosclerotic aortic tissue.7 Recently, we have demonstrated that hypercholesterolemia in pigs resulted in elevated plasma endothelin concentrations and enhanced coronary artery tissue endothelin immunoreactivity. Intracoronary administration of acetylcholine further increased plasma endothelin only in the hypercholesterolemic pigs in association with coronary vasoconstriction.13 The present study extends our previous observations and demonstrates that circulating and coronary endothelin are enhanced early in the evolution of human coronary atherosclerosis and coexist with abnormal endothelial function. Moreover, the current study is in accordance with a previous study by Toyo-oka and colleagues,5 who demonstrated elevated ET-1 concentrations in patients with vasospastic angina. The increased endothelin concentrations in patients with endothelial dysfunction may represent enhanced production and release of endothelin by the vascular wall during the evolution of the atherogenic process. This observation is supported by in vitro studies that demonstrated that proatherogenic factors such as oxidized LDL17 may induce endothelin production and release and that ET-1 mRNA expression is elevated in atherosclerotic lesions.18
Several studies have demonstrated that the presence of early atherosclerosis and coronary risk factors are characterized by coronary epicardial and resistance vessel endothelial dysfunction.19 20 However, the precise mechanisms underlying impaired endothelial dysfunction cannot be deduced from these studies. Zeiher et al19 and Egashira et al20 suggested that impaired resistance coronary endothelial function may be secondary to increased concentrations of vasoconstricting substances that may be activated at the atherosclerotic lesions21 or, alternatively, that the dilator effect of acetylcholine is counteracted by the concomitant release of an endothelium-derived constricting factor.22 The observations in our current study are in accord with these suggestive mechanisms. It may be speculated that during early coronary atherosclerosis, an imbalance between production and release of EDRF and endothelin occurs that leads to augmented production and release of endothelin and potentiation of its vasoconstrictive actions.4 This hypothesis is supported by the current study, which demonstrates decreased levels of coronary cGMP in humans with coronary endothelial dysfunction, and by previous studies demonstrating in vivo that the vasoconstrictor actions of endothelin are augmented by simultaneous inhibition of EDRF synthesis with NG-monomethyl-L-arginine.23 Furthermore, enhanced endothelin immunoreactivity in the coronary circulation may mediate vasoconstriction and sensitize the coronary vascular smooth muscle to other vasoconstrictive factors, such as angiotensin II and catecholamines.24 25 26 Thus, the increased concentrations of the potent vasoconstrictor endothelin together with reduced EDRF activity lead to altered coronary endothelial function.
Although patients with impaired renal function were excluded from the study and there was no difference in serum creatinine between the groups, we cannot exclude the possibility that subtle changes in creatinine clearance and hence in endothelin clearance may contribute to the difference in plasma endothelin between the groups.
The current study demonstrates that coronary cGMP concentrations are suppressed in humans with coronary endothelial dysfunction and elevated endothelin concentrations. Intracoronary administration of acetylcholine increased coronary cGMP only in the patients with an intact endothelial response to acetylcholine, while in the group of patients with a coronary vasoconstriction response to acetylcholine, no changes in coronary cGMP concentrations were observed. This observation complements previous in vitro studies that demonstrated that in response to acetylcholine, the accumulation of cGMP in human coronary atherosclerotic strips was suppressed compared with nonatherosclerotic strips.27 Furthermore, endothelin attenuates nitric oxide–induced cGMP generation in vitro.28 The increase in coronary cGMP generation in response to intracoronary nitroglycerin was similar between the groups. This observation may reflect abnormality only at the level of the endothelial cells while the smooth muscle cell response remains intact.
The mechanism for the increase in coronary endothelin concentrations in response to intracoronary acetylcholine may be multifactorial. It may be speculated that in pathophysiological states with functional alteration of the endothelium, acetylcholine may release endothelin rather than EDRF. This latter hypothesis is supported by previous studies that demonstrated that several agonists such as thrombin stimulate simultaneous release of EDRF and endothelin1 29 and that atherosclerosis impairs endothelium-dependent vascular relaxation to acetylcholine and thrombin.30 Moreover, the current study extends our previous observation that intracoronary acetylcholine in the hypercholesterolemic pig further increases plasma endothelin and is associated with coronary vasoconstriction.13 An alternative hypothesis is that endothelin may be released secondary to coronary vasoconstriction induced by acetylcholine and may be related to tissue hypoxia, decreased shear stress, and myocardial ischemia and reperfusion, all of which stimulate endothelin release from the coronary vascular bed.31 32 33
The rapid release of endothelin into the coronary circulation is consistent with recent observations that endothelin may be released acutely in vitro after mechanical stretch34 and also in vivo after balloon dilation.35
The increase in coronary endothelin concentrations following acetylcholine administration may play an important physiological and pathophysiological role in the regulation of coronary flow because a low dose of intracoronary endothelin produces significant coronary constriction and myocardial ischemia.11 12 It seems reasonable to consider that endothelins act primarily as local, paracrine/autocrine hormones36 and that the coronary circulating levels observed in our study underestimate the local and tissue concentrations of coronary endothelins. Although we have an increasingly better understanding of the causal role of endothelins in diseases involving abnormal vasoconstriction, the current study provides more biological insight toward a novel target for therapeutic intervention, such as endothelin receptor antagonists or specific endothelin-converting enzyme inhibitors.36
In summary, the present study demonstrates that early coronary atherosclerosis in humans is characterized by increased coronary and circulating endothelin and decreased coronary EDRF second messenger and cGMP concentrations and is associated with coronary endothelial dysfunction. In response to intracoronary acetylcholine, a further increase in coronary endothelin concentration was observed and was associated with the degree of coronary vasoconstriction. This study advances the concept that endothelial dysfunction and atherosclerosis are characterized by an imbalance between endothelium-derived vasodilating and vasoconstricting factors. This study also strongly supports a role for endothelin as an early participant in and marker for coronary atherosclerosis and coronary endothelial dysfunction in humans.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by grants from the National Institutes of Health (HL-03180-01), Minnesota Affiliate of the American Heart Association, and Mayo Foundation.
Received February 1, 1995; revision received April 13, 1995; accepted June 4, 1995.
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 P. H. McNulty, M. A. Tulli, B. J. Robertson, V. Lendel, L. A. Harach, S. Scott, and J. P. Boehmer Effect of simulated postprandial hyperglycemia on coronary blood flow in cardiac transplant recipients Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H103 - H108. [Abstract] [Full Text] [PDF]
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 E. Y. Lai, A. E. G. Persson, B. Bodin, O. Kallskog, A. Andersson, U. Pettersson, P. Hansell, and L. Jansson Endothelin-1 and pancreatic islet vasculature: studies in vivo and on isolated, vascularly perfused pancreatic islets Am J Physiol Endocrinol Metab, June 1, 2007; 292(6): E1616 - E1623. [Abstract] [Full Text] [PDF]
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 S. Lavi, J. P. McConnell, C. S. Rihal, A. Prasad, V. Mathew, L. O. Lerman, and A. Lerman Local Production of Lipoprotein-Associated Phospholipase A2 and Lysophosphatidylcholine in the Coronary Circulation: Association With Early Coronary Atherosclerosis and Endothelial Dysfunction in Humans Circulation, May 29, 2007; 115(21): 2715 - 2721. [Abstract] [Full Text] [PDF]
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S. Lavi, A. Prasad, E. H. Yang, V. Mathew, R. D. Simari, C. S. Rihal, L. O. Lerman, and A. Lerman Smoking Is Associated With Epicardial Coronary Endothelial Dysfunction and Elevated White Blood Cell Count in Patients With Chest Pain and Early Coronary Artery Disease Circulation, May 22, 2007; 115(20): 2621 - 2627. [Abstract] [Full Text] [PDF]
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 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]
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 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]
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 G. Muller, R. A. Catar, B. Niemann, M. Barton, L. Knels, M. Wendel, and H. Morawietz Upregulation of endothelin receptor B in human endothelial cells by low-density lipoproteins. Experimental Biology and Medicine, June 1, 2006; 231(6): 766 - 771. [Abstract] [Full Text] [PDF]
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 T. Pfab, C. Thone-Reineke, F. Theilig, I. Lange, H. Witt, C. Maser-Gluth, M. Bader, J.-P. Stasch, P. Ruiz, S. Bachmann, et al. Diabetic Endothelin B Receptor-Deficient Rats Develop Severe Hypertension and Progressive Renal Failure J. Am. Soc. Nephrol., April 1, 2006; 17(4): 1082 - 1089. [Abstract] [Full Text] [PDF]
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J. Madaric, J. Bartunek, K. Verhamme, M. Penicka, E. Van Schuerbeeck, P. Nellens, G. R. Heyndrickx, W. Wijns, M. Vanderheyden, and B. De Bruyne Hyperdynamic Myocardial Response to Beta-Adrenergic Stimulation in Patients With Chest Pain and Normal Coronary Arteries J. Am. Coll. Cardiol., October 4, 2005; 46(7): 1270 - 1275. [Abstract] [Full Text] [PDF]
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Y.-M. Go and D. P. Jones Intracellular Proatherogenic Events and Cell Adhesion Modulated by Extracellular Thiol/Disulfide Redox State Circulation, June 7, 2005; 111(22): 2973 - 2980. [Abstract] [Full Text] [PDF]
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R. D. Shipley and J. M. Muller-Delp Aging decreases vasoconstrictor responses of coronary resistance arterioles through endothelium-dependent mechanisms Cardiovasc Res, May 1, 2005; 66(2): 374 - 383. [Abstract] [Full Text] [PDF]
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 S. F. van Eeden, A. Yeung, K. Quinlam, and J. C. Hogg Systemic Response to Ambient Particulate Matter: Relevance to Chronic Obstructive Pulmonary Disease Proceedings of the ATS, April 1, 2005; 2(1): 61 - 67. [Abstract] [Full Text] [PDF]
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A. R. Chade, J. Herrmann, X. Zhu, J. D. Krier, A. Lerman, and L. O. Lerman Effects of Proteasome Inhibition on the Kidney in Experimental Hypercholesterolemia J. Am. Soc. Nephrol., April 1, 2005; 16(4): 1005 - 1012. [Abstract] [Full Text] [PDF]
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C. L. Heaps, D. L. Tharp, and D. K. Bowles Hypercholesterolemia abolishes voltage-dependent K+ channel contribution to adenosine-mediated relaxation in porcine coronary arterioles Am J Physiol Heart Circ Physiol, February 1, 2005; 288(2): H568 - H576. [Abstract] [Full Text] [PDF]
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 C. P. del Villar, C. J. G. Alonso, C. A. Feldstein, L. A. Juncos, and J. C. Romero Role of Endothelin in the Pathogenesis of Hypertension Mayo Clin. Proc., January 1, 2005; 80(1): 84 - 96. [Abstract] [PDF]
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J. Herrmann, S. T. Higano, R. J. Lenon, C. S. Rihal, and A. Lerman Myocardial bridging is associated with alteration in coronary vasoreactivity Eur. Heart J., December 1, 2004; 25(23): 2134 - 2142. [Abstract] [Full Text] [PDF]
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S. C. Halligan, B. Murtagh, R. J. Lennon, G. M. Pumper, V. Mathew, S. T. Higano, and A. Lerman Effect of Long-term Hormone Replacement Therapy on Coronary Endothelial Function in Postmenopausal Women Mayo Clin. Proc., December 1, 2004; 79(12): 1514 - 1520. [Abstract] [PDF]
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M. E. Widlansky, N. Gokce, J. F. Keaney Jr, and J. A. Vita The clinical implications of endothelial dysfunction J. Am. Coll. Cardiol., October 1, 2003; 42(7): 1149 - 1160. [Abstract] [Full Text] [PDF]
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 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]
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P.O Bonetti, L.O Lerman, C Napoli, and A Lerman Statin effects beyond lipid lowering--are they clinically relevant? Eur. Heart J., February 1, 2003; 24(3): 225 - 248. [Full Text] [PDF]
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 P. O. Bonetti, L. O. Lerman, and A. Lerman Endothelial Dysfunction: A Marker of Atherosclerotic Risk Arterioscler Thromb Vasc Biol, February 1, 2003; 23(2): 168 - 175. [Abstract] [Full Text] [PDF]
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P. Piatti, G. Fragasso, L. D. Monti, E. Setola, P. Lucotti, I. Fermo, R. Paroni, E. Galluccio, G. Pozza, S. Chierchia, et al. Acute Intravenous l-Arginine Infusion Decreases Endothelin-1 Levels and Improves Endothelial Function in Patients With Angina Pectoris and Normal Coronary Arteriograms: Correlation With Asymmetric Dimethylarginine Levels Circulation, January 28, 2003; 107(3): 429 - 436. [Abstract] [Full Text] [PDF]
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 G. Ahlborg and J. Lindstrom Insulin sensitivity and big ET-1 conversion to ET-1 after ETA- or ETB-receptor blockade in humans J Appl Physiol, December 1, 2002; 93(6): 2112 - 2121. [Abstract] [Full Text] [PDF]
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L. V d'Uscio, M. Barton, S. Shaw, and T. F Luscher Chronic ETA receptor blockade prevents endothelial dysfunction of small arteries in apolipoprotein E-deficient mice Cardiovasc Res, February 1, 2002; 53(2): 487 - 495. [Abstract] [Full Text] [PDF]
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A. Saitta, D. Altavilla, D. Cucinotta, N. Morabito, N. Frisina, F. Corrado, R. D'Anna, A. Lasco, G. Squadrito, A. Gaudio, et al. Randomized, Double-Blind, Placebo-Controlled Study on Effects of Raloxifene and Hormone Replacement Therapy on Plasma NO Concentrations, Endothelin-1 Levels, and Endothelium-Dependent Vasodilation in Postmenopausal Women Arterioscler Thromb Vasc Biol, September 1, 2001; 21(9): 1512 - 1519. [Abstract] [Full Text] [PDF]
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P. A. MacCarthy, N. C. Pegge, B. D. Prendergast, A. M. Shah, and P. H. Groves The physiological role of endogenous endothelin in the regulation of human coronary vasomotor tone J. Am. Coll. Cardiol., January 1, 2001; 37(1): 137 - 143. [Abstract] [Full Text] [PDF]
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T. F. Luscher and M. Barton Endothelins and Endothelin Receptor Antagonists : Therapeutic Considerations for a Novel Class of Cardiovascular Drugs Circulation, November 7, 2000; 102(19): 2434 - 2440. [Abstract] [Full Text] [PDF]
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M. Takamura, R. Parent, P. Cernacek, and M. Lavallee Influence of dual ETA/ETB-receptor blockade on coronary responses to treadmill exercise in dogs J Appl Physiol, November 1, 2000; 89(5): 2041 - 2048. [Abstract] [Full Text] [PDF]
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C. M. Webb, M. A. Ghatei, J. G. McNeill, DCRR, and P. Collins 17{beta}-Estradiol Decreases Endothelin-1 Levels in the Coronary Circulation of Postmenopausal Women With Coronary Artery Disease Circulation, October 3, 2000; 102(14): 1617 - 1622. [Abstract] [Full Text] [PDF]
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P. A. Kaufmann, T. Gnecchi-Ruscone, K. P. Schafers, T. F. Luscher, and P. G. Camici Low density lipoprotein cholesterol and coronary microvascular dysfunction in hypercholesterolemia J. Am. Coll. Cardiol., July 1, 2000; 36(1): 103 - 109. [Abstract] [Full Text] [PDF]
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H. Morawietz, R. Talanow, M. Szibor, U. Rueckschloss, A. Schubert, B. Bartling, D. Darmer, and J. Holtz Regulation of the endothelin system by shear stress in human endothelial cells J. Physiol., June 15, 2000; 525(3): 761 - 770. [Abstract] [Full Text] [PDF]
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S. Hamasaki, J. Al Suwaidi, S. T. Higano, K. Miyauchi, D. R. Holmes Jr., and A. Lerman Attenuated coronary flow reserve and vascular remodeling in patients with hypertension and left ventricular hypertrophy J. Am. Coll. Cardiol., May 1, 2000; 35(6): 1654 - 1660. [Abstract] [Full Text] [PDF]
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J. A. Suwaidi, S. Hamasaki, S. T. Higano, R. A. Nishimura, D. R. Holmes Jr, and A. Lerman Long-Term Follow-Up of Patients With Mild Coronary Artery Disease and Endothelial Dysfunction Circulation, March 7, 2000; 101(9): 948 - 954. [Abstract] [Full Text] [PDF]
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S. Hamasaki, S. T. Higano, J. A. Suwaidi, R. A. Nishimura, K. Miyauchi, D. R. Holmes Jr, and A. Lerman Cholesterol-Lowering Treatment Is Associated With Improvement in Coronary Vascular Remodeling and Endothelial Function in Patients With Normal or Mildly Diseased Coronary Arteries Arterioscler Thromb Vasc Biol, March 1, 2000; 20(3): 737 - 743. [Abstract] [Full Text] [PDF]
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J. M. Mostaza, M. V. Gomez, F. Gallardo, M. L. Salazar, R. Martin-Jadraque, L. Plaza-Celemin, I. Gonzalez-Maqueda, and L. Martin-Jadraque Cholesterol reduction improves myocardial perfusion abnormalities in patients with coronary artery disease and average cholesterol levels J. Am. Coll. Cardiol., January 1, 2000; 35(1): 76 - 82. [Abstract] [Full Text] [PDF]
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H. Drexler Nitric oxide and coronary endothelial dysfunction in humans Cardiovasc Res, August 15, 1999; 43(3): 572 - 579. [Full Text] [PDF]
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I. D. Cox, H. E. Botker, J. P. Bagger, H. S. Sonne, B. O Kristensen, and J. C. Kaski Elevated endothelin concentrations are associated with reduced coronary vasomotor responses in patients with chest pain and normal coronary arteriograms J. Am. Coll. Cardiol., August 1, 1999; 34(2): 455 - 460. [Abstract] [Full Text] [PDF]
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 C. Lowbeer, A. Ottosson-Seeberger, S. A. Gustafsson, R. Norrman, J. Hulting, and A. Gutierrez Increased cardiac troponin T and endothelin-1 concentrations in dialysis patients may indicate heart disease Nephrol. Dial. Transplant., August 1, 1999; 14(8): 1948 - 1955. [Abstract] [Full Text] [PDF]
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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]
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J. Maruyama, A. Yokochi, K. Maruyama, and S. Nosaka Acetylcholine-induced endothelium-derived contracting factor in hypoxic pulmonary hypertensive rats J Appl Physiol, May 1, 1999; 86(5): 1687 - 1695. [Abstract] [Full Text] [PDF]
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A. OTTOSSON-SEEBERGER, G. AHLBORG, A. HEMSÉN, J. M. LUNDBERG, and A. ALVESTRAND Hemodynamic Effects of Endothelin-1 and Big Endothelin-1 in Chronic Hemodialysis Patients J. Am. Soc. Nephrol., May 1, 1999; 10(5): 1037 - 1044. [Abstract] [Full Text]
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L. Tiret, O. Poirier, V. Hallet, T. A. McDonagh, C. Morrison, J. J. V. McMurray, H. J. Dargie, D. Arveiler, J.-B. Ruidavets, G. Luc, et al. The Lys198Asn Polymorphism in the Endothelin-1 Gene Is Associated With Blood Pressure in Overweight People Hypertension, May 1, 1999; 33(5): 1169 - 1174. [Abstract] [Full Text] [PDF]
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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]
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 P. Poredos, M. Orehek, E. Tratnik, and P. Poredos Smoking is Associated with Dose-Related Increase of Intima-Media Thickness and Endothelial Dysfunction Angiology, March 1, 1999; 50(3): 201 - 208. [Abstract] [PDF]
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I. Anwaar, A. Gottsater, F. Lindgarde, and I. Mattiasson Increasing Plasma Neopterin and Persistent Plasma Endothelin During Follow-up After Acute Cerebral Ischemia Angiology, January 1, 1999; 50(1): 1 - 8. [Abstract] [PDF]
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P. R. A. Caramori, A. G. Adelman, E. R. Azevedo, G. E. Newton, A. B. Parker, and J. D. Parker Therapy with nitroglycerin increases coronary vasoconstriction in response to acetylcholine J. Am. Coll. Cardiol., December 1, 1998; 32(7): 1969 - 1974. [Abstract] [Full Text] [PDF]
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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]
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 J. K. Liao Endothelium and acute coronary syndromes Clin. Chem., August 1, 1998; 44(8): 1799 - 1808. [Abstract] [Full Text] [PDF]
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A. Lerman, J. C. Burnett Jr, S. T. Higano, L. J. McKinley, and D. R. Holmes Jr Long-term L-Arginine Supplementation Improves Small-Vessel Coronary Endothelial Function in Humans Circulation, June 2, 1998; 97(21): 2123 - 2128. [Abstract] [Full Text] [PDF]
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 P C Smits, L Bos, M A Q. van Ufford, F D Eefting, G Pasterkamp, and C Borst Shrinkage of human coronary arteries is an important determinant of de novo atherosclerotic luminal stenosis: an in vivo intravascular ultrasound study Heart, February 1, 1998; 79(2): 143 - 147. [Abstract] [Full Text]
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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]
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D. Hasdai, R. J. Gibbons, D. R. Holmes Jr, S. T. Higano, and A. Lerman Coronary Endothelial Dysfunction in Humans Is Associated With Myocardial Perfusion Defects Circulation, November 18, 1997; 96(10): 3390 - 3395. [Abstract] [Full Text]
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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]
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O. Tamai, H. Matsuoka, H. Itabe, Y. Wada, K. Kohno, and T. Imaizumi Single LDL Apheresis Improves Endothelium-Dependent Vasodilatation in Hypercholesterolemic Humans Circulation, January 7, 1997; 95(1): 76 - 82. [Abstract] [Full Text]
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