Faculty Collaboration Database

Long-term administration of endothelin receptor antagonist improves coronary endothelial function in patients with early atherosclerosis. Circulation 2010 Sep 07;122(10):958-66

Date

08/25/2010

Pubmed ID

20733096

Pubmed Central ID

PMC2946239

DOI

10.1161/CIRCULATIONAHA.110.967406

Scopus ID

2-s2.0-77957289366 (requires institutional sign-in at Scopus site)   132 Citations

Abstract

BACKGROUND: 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.

METHODS AND RESULTS: 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.

CONCLUSIONS: 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: http://www.clinicaltrials.gov. Unique identifier: NCT00271492.

Author List

Reriani M, Raichlin E, Prasad A, Mathew V, Pumper GM, Nelson RE, Lennon R, Rihal C, Lerman LO, Lerman A

Author

Eugenia Raichlin MD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Blood Glucose
Blood Pressure
Coronary Artery Disease
Coronary Circulation
Endothelin-1
Endothelium, Vascular
Enzyme Inhibitors
Female
Follow-Up Studies
Heart Rate
Humans
Kidney
Lipoprotein(a)
Male
Microcirculation
Middle Aged
Nitric Oxide
Pyrrolidines
Receptor, Endothelin A
Triglycerides
Uric Acid
omega-N-Methylarginine