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: 14.43). 09/2010; 122(10):958-66. DOI: 10.1161/CIRCULATIONAHA.110.967406
Source: PubMed


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.

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Available from: Eugenia Raichlin, Jan 31, 2014
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    • "In agreement, a recent meta-analysis in OSA patients reported that continuous positive airway pressure (CPAP) treatment significantly increases BMI and body weight (Drager et al., 2015). Also relevant to the present study, there is clinical evidence that circulating ET-1 levels are elevated in OSA patients and are normalised by CPAP treatment (Jordan et al., 2005; Gjorup et al., 2007) and that triglyceride levels were improved in patients treated with atrasantan, an ET-1 receptor antagonist (Reriani et al., 2010). Similarly, in favour of a role of endothelin in the metabolic response to IH, we observed that bosentan treatment partially reversed fat loss and improved weight gain. "
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    ABSTRACT: Obstructive sleep apnea syndrome (OSA) is characterized by repetitive episodes of upper airway collapse during sleep resulting in chronic intermittent hypoxia (IH). OSA, through IH, promotes cardiovascular and metabolic disorders. Endothelin-1 (ET-1) secretion is upregulated by IH, and is able to modulate adipocyte metabolism. Therefore, our goal was to characterize the role of ET-1 in the metabolic consequences of IH on adipose tissue in vivo and in vitro. Wistar rats were submitted to 14 days of IH-cycles (30 s 21% FiO2 - 30 s 5% FiO2 , 8 h day(-1) ) or normoxia (air-air cycles) and were treated or not with bosentan, a dual type A and B endothelin receptor (ETA-R and ETB-R) antagonist. Bosentan treatment decreased plasma FFA and triglycerides levels, and inhibited IH-induced lipolysis in adipose tissue. Moreover, IH induced a 2-fold increase in ET-1 transcription and ETA-R expression in adipose tissue that was reversed by bosentan. In 3T3-L1 adipocytes, ET-1 upregulated its own and its ETA-R transcription and this effect was abolished by bosentan. Moreover, ET-1 induced glycerol release and inhibited insulin-induced glucose uptake. Bosentan and BQ123 inhibited these effects. Bosentan also reversed the ET-1-induced phosphorylation of hormone-sensitive lipase (HSL) on Ser(660) . Finally, ET-1-induced lipolysis and HSL phosphorylation were also observed under hypoxia. Altogether, these data suggest that ET-1 is involved in IH-induced lipolysis in Wistar rats, and that upregulation of ET-1 production and ETA-R expression by ET-1 itself under IH could amplify its effects. Moreover, ET-1-induced lipolysis could be mediated through ETA-R and the activation of HSL by Ser(660) phosphorylation. This article is protected by copyright. All rights reserved.
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    • "Indeed, both oxidative stress and increased ET-1 bioactivity have been implicated in age-dependent impaired endothelial cell function (Barton, 2010; Seals et al., 2011), which is associated with arterial stiffening and sclerosis (Zieman et al., 2005), and consecutive renal injury (Zhou et al., 2008). Antagonizing ET-1-dependent effects have previously been found to improve endothelial function in individuals with early coronary artery disease (Reriani et al., 2010), and even to reverse renal aging and glomerular vascular injury (Ortmann et al., 2004). Moreover, treatment with an ET A receptor antagonist reduces arterial stiffness in patients with chronic kidney disease (Dhaun et al., 2009). "
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