Long-term administration of endothelin receptor antagonist improves coronary endothelial function in patients with early atherosclerosis.
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.


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.
Reriani
Martin
M
Division of Cardiovascular Diseases, Mayo Clinic Rochester, 200 First St SW, Rochester, MN 55905, USA.
Raichlin
Eugenia
E
Prasad
Abhiram
A
Mathew
Verghese
V
Pumper
Geralyn M
GM
Nelson
Rebecca E
RE
Lennon
Ryan
R
Rihal
Charanjit
C
Lerman
Lilach O
LO
Lerman
Amir
A
D000328:Adult; D000077868:Atrasentan; D001786:Blood Glucose / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D003324:Coronary Artery Disease / Q000188:drug therapy* / Q000378:metabolism; D003326:Coronary Circulation / Q000187:drug effects; D019332:Endothelin-1 / Q000037:antagonists & inhibitors*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000187:drug effects; D017270:Lipoprotein(a) / Q000097:blood; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D011759:Pyrrolidines / Q000008:administration & dosage* / Q000009:adverse effects; D044022:Receptor, Endothelin A / Q000378:metabolism; D014280:Triglycerides / Q000097:blood; D014527:Uric Acid / Q000097:blood; D019323:omega-N-Methylarginine / Q000008:administration & dosage
D001786:Blood Glucose; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D017270:Lipoprotein(a); D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D014280:Triglycerides; D014527:Uric Acid; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D000077868:Atrasentan