Long-Term Administration of Endothelin Receptor Antagonist Improves Coronary Endothelial Function in Patients With Early Atherosclerosis

Division of Cardiovascular Diseases, Mayo Clinic Rochester, 200 First St SW, Rochester, MN 55905, USA.
Circulation (Impact Factor: 14.95). 09/2010; 122(10):958-66. DOI: 10.1161/CIRCULATIONAHA.110.967406
Source: PubMed

ABSTRACT Endothelin (ET-1) is one of the most potent vasoconstrictors and plays a seminal role in the pathogenesis of atherosclerosis. The present study was designed to test the hypothesis that long-term treatment with an endothelin-A (ET(A)) receptor antagonist improves coronary endothelial function in patients with early coronary atherosclerosis.
Forty-seven patients with multiple cardiovascular risk factors, nonobstructive coronary artery disease, and coronary endothelial dysfunction were randomized in a double-blind manner to either the ET(A) receptor antagonist atrasentan (10 mg) or placebo for 6 months. Coronary endothelium-dependent vasodilation was examined by infusing acetylcholine (10(-6) to 10(-4) mol/L) in the left anterior descending coronary artery. N(G)-monomethyl-l-arginine was administered to a subgroup of patients. Endothelium-independent coronary flow reserve was examined by use of intracoronary adenosine and nitroglycerin. Baseline characteristics and incidence of adverse effects were similar between the 2 groups. There was a significant improvement in percent change of coronary blood flow in response to acetylcholine at 6 months from baseline in the atrasentan group compared with the placebo group (39.67%, 95% confidence interval 23.23% to 68.21%, versus -2.22%, 95% confidence interval -27.37% to 15.28%; P<0.001). No significant difference in the percent change of coronary artery diameter or change in coronary flow reserve was demonstrated. Coronary blood flow, coronary artery diameter, and the effect of N(G)-monomethyl-l-arginine were similar between the groups at baseline and at 6 months.
This study demonstrates that 6-month treatment with atrasentan improves coronary microvascular endothelial function and supports the role of the endogenous endothelin system in the regulation of endothelial function in early atherosclerosis in humans. Clinical Trial Registration Information- URL: Unique identifier: NCT00271492.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective Test the hypothesis that exercise training would increase endothelin-mediated vasoconstriction in collateral-dependent arteries via enhanced contribution of ETA.Methods An ameroid constrictor was surgically placed around the proximal LCX artery to induce gradual occlusion in Yucatan miniature swine. Eight-weeks postoperatively, pigs were randomized into sedentary or exercise-training (treadmill; 5 days/wk; 14 wks) groups. Subsequently, arteries (~150 μm diameter) were isolated from collateral-dependent and nonoccluded myocardial regions and studied.ResultsFollowing exercise training, ET-1-mediated contraction was significantly enhanced in collateral-dependent arteries. Exercise training induced a disproportionate increase in the ETA contribution to the ET-1 contractile response in collateral-dependent arteries, with negligible contributions by ETB. In collateral-dependent arteries of sedentary pigs, inhibition of ETA or ETB did not significantly alter ET-1 contractile responses in collateral-dependent arteries, suggesting compensation by the functionally active receptor. These adaptations occurred without significant changes in ETA, ETB, or ECE mRNA levels but with significant exercise training-induced elevations in endothelin levels in both nonoccluded and collateral-dependent myocardial regionsConclusions Taken together, these data reveal differential adaptive responses in collateral-dependent arteries based upon physical activity level. ETA and ETB appear to compensate for one another to maintain contraction in sedentary pigs, whereas exercise-training favors enhanced contribution of ETA.This article is protected by copyright. All rights reserved.
    Microcirculation (New York, N.Y.: 1994) 09/2014; 22(1). DOI:10.1111/micc.12174 · 2.37 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Erectile dysfunction (ED) is associated with an increased risk for cardiovascular disease, stroke, and all-cause mortality, independent of conventional cardiovascular risk factors. Coronary endothelial dysfunction is independently associated with ED in men with early coronary atherosclerosis. We aimed to investigate whether coronary microvascular dysfunction predicts development of ED in patients presenting with coronary atherosclerosis without critical stenoses.
    Coronary Artery Disease 07/2014; 25(7). DOI:10.1097/MCA.0000000000000145 · 1.30 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Endothelin-1 (ET-1) is a potent endogenous vasoconstrictor, mainly secreted by endothelial cells. It acts through two types of receptors: ETA and ETB. Apart from a vasoconstrictive action, ET-1 causes fibrosis of the vascular cells and stimulates production of reactive oxygen species. It is claimed that ET-1 induces proinflammatory mechanisms, increasing superoxide anion production and cytokine secretion. A recent study has shown that ET-1 is involved in the activation of transcription factors such as NF-κB and expression of proinflammatory cytokines including TNF-α, IL-1, and IL-6. It has been also indicated that during endotoxaemia, the plasma level of ET-1 is increased in various animal species. Some authors indicate a clear correlation between endothelin plasma level and morbidity/mortality rate in septic patients. These pathological effects of ET-1 may be abrogated at least partly by endothelin receptor blockade. ET-1 receptor antagonists may be useful for prevention of various vascular diseases. This review summarises the current knowledge regarding endothelin receptor antagonists and the role of ET-1 in sepsis and inflammation.
    Archivum Immunologiae et Therapiae Experimentalis 10/2014; 63(1). DOI:10.1007/s00005-014-0310-1 · 2.38 Impact Factor

Full-text (2 Sources)

Available from
Jun 4, 2014