Endothelin in coronary endothelial dysfunction and early atherosclerosis in humans.

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.

[1]  P. Vigne,et al.  Cross Talk Among Cyclic AMP, Cyclic GMP, and Ca2+ ‐Dependent Intracellular Signalling Mechanisms in Brain Capillary Endothelial Cells , 1994, Journal of neurochemistry.

[2]  J. Vane,et al.  Endothelin-1 release from endothelial cells in culture is elevated both acutely and chronically by short periods of mechanical stretch. , 1994, Biochemical and biophysical research communications.

[3]  M. Yanagisawa.  The endothelin system. A new target for therapeutic intervention. , 1994, Circulation.

[4]  V. Fuster,et al.  Circulating and Tissue Endothelin Immunoreactivit in Hypercholesterolemic Pigs , 1993, Circulation.

[5]  A M Zeiher,et al.  Endothelium-mediated coronary blood flow modulation in humans. Effects of age, atherosclerosis, hypercholesterolemia, and hypertension. , 1993, The Journal of clinical investigation.

[6]  P. Libby,et al.  Endothelin-1 and endothelin receptor mRNA expression in normal and atherosclerotic human arteries. , 1993, Biochemical and biophysical research communications.

[7]  M. Sugimachi,et al.  Impaired coronary blood flow response to acetylcholine in patients with coronary risk factors and proximal atherosclerotic lesions. , 1993, The Journal of clinical investigation.

[8]  F. Crea,et al.  Myocardial ischemia caused by distal coronary vasoconstriction. , 1992, The American journal of cardiology.

[9]  G. Bilder,et al.  Modulation of vascular reactivity by vasoactive peptides in aortic rings from hypercholesterolemic rabbits. , 1992, European journal of pharmacology.

[10]  M. Kohzuki,et al.  Endothelin-1 augments pressor response to angiotensin II infusion in rats. , 1992, Hypertension.

[11]  T. Lüscher,et al.  Oxidized low density lipoproteins induce mRNA expression and release of endothelin from human and porcine endothelium. , 1992, Circulation research.

[12]  A. Lerman,et al.  Inhibition of Endothelium‐Derived Relaxing Factor Enhances Endothelin‐Mediated Vasoconstriction , 1992, Circulation.

[13]  V. Fuster,et al.  The pathogenesis of coronary artery disease and the acute coronary syndromes (2). , 1992, The New England journal of medicine.

[14]  A. Lerman,et al.  Intact and altered endothelium in regulation of vasomotion. , 1992, Circulation.

[15]  M. Kohno,et al.  Circulating immunoreactive endothelin in patients undergoing percutaneous transluminal coronary angioplasty. , 1991, Metabolism: clinical and experimental.

[16]  A. Lerman,et al.  Circulating and tissue endothelin immunoreactivity in advanced atherosclerosis. , 1991, The New England journal of medicine.

[17]  D. Faller,et al.  Hypoxia induces endothelin gene expression and secretion in cultured human endothelium. , 1991, The Journal of clinical investigation.

[18]  K. Margulies,et al.  Endothelium-derived relaxing factor in regulation of basal cardiopulmonary and renal function. , 1991, The American journal of physiology.

[19]  S. Diamond,et al.  Fluid flow decreases preproendothelin mRNA levels and suppresses endothelin-1 peptide release in cultured human endothelial cells. , 1991, Journal of vascular surgery.

[20]  T. Lüscher,et al.  Hirudin and nitrates inhibit the thrombin-induced release of endothelin from the intact porcine aorta. , 1991, Circulation research.

[21]  A. Lerman,et al.  Endothelin Has Biological Actions at Pathophysiological Concentrations , 1991, Circulation.

[22]  M. Yanagisawa,et al.  Increased plasma level of endothelin-1 and coronary spasm induction in patients with vasospastic angina pectoris. , 1991, Circulation.

[23]  H. Drexler,et al.  Modulation of coronary vasomotor tone in humans. Progressive endothelial dysfunction with different early stages of coronary atherosclerosis. , 1991, Circulation.

[24]  K. Margulies,et al.  Endothelin: a new cardiovascular regulatory peptide. , 1990, Mayo Clinic proceedings.

[25]  T. Lüscher,et al.  Activation of endothelial L-arginine pathway in resistance arteries. Effect of age and hypertension. , 1990, Hypertension.

[26]  L. V. von Segesser,et al.  Threshold concentrations of endothelin-1 potentiate contractions to norepinephrine and serotonin in human arteries. A new mechanism of vasospasm? , 1990, Circulation.

[27]  S. Oparil,et al.  Atrial Natriuretic Factor Prevents NaCl‐Sensitive Hypertension in Spontaneously Hypertensive Rats , 1990, Hypertension.

[28]  Y. Hirata,et al.  Endothelin is a potent mitogen for rat vascular smooth muscle cells. , 1989, Atherosclerosis.

[29]  Y. Yazaki,et al.  Hemodynamic shear stress stimulates endothelin production by cultured endothelial cells. , 1989, Biochemical and biophysical research communications.

[30]  M. Redfield,et al.  Integrated cardiac, renal, and endocrine actions of endothelin. , 1989, The Journal of clinical investigation.

[31]  R. Frye,et al.  Vasoconstrictor activity of coronary sinus plasma from patients with coronary artery disease. , 1987, Journal of the American College of Cardiology.

[32]  P. D. Henry,et al.  Impaired muscarinic endothelium-dependent relaxation and cyclic guanosine 5'-monophosphate formation in atherosclerotic human coronary artery and rabbit aorta. , 1987, The Journal of clinical investigation.

[33]  D. Harrison,et al.  Atherosclerosis Impairs Endothelium‐Dependent Vascular Relaxation to Acetylcholine and Thrombin in Primates , 1986, Circulation research.

[34]  D. Holmes,et al.  Estimation of the effects of angioplasty on coronary stenosis using quantitative video angiography. , 1985, Catheterization and cardiovascular diagnosis.

[35]  C W Parker,et al.  Radioimmunoassay for cyclic nucleotides. I. Preparation of antibodies and iodinated cyclic nucleotides. , 1972, The Journal of biological chemistry.