Chronic endothelin receptor antagonism preserves coronary endothelial function in experimental hypercholesterolemia.
BACKGROUND
Endothelin-1 (ET-1) is an endothelium-derived peptide that constricts coronary vessels through stimulation of the ET-A and ET-B receptors. Experimental porcine hypercholesterolemia is associated with impaired coronary endothelial function and elevated ET-1 concentrations. This study was designed to test the hypothesis that chronic endothelin receptor antagonism preserves coronary endothelial function in experimental hypercholesterolemia.


RESULTS
Acetylcholine (10(-6) to 10(-4) mol/L) was serially infused into the left anterior descending coronary artery in pigs at baseline and after 12 weeks of a high-cholesterol diet. In the interim, the animals were randomized to 3 groups: Group 1 received no therapy, group 2 received 3 mg/kg per day RO 48-5695, a combined ET-A/ET-B receptor antagonist, and group 3 received 4 mg/kg per day ABT-627, a selective ET-A receptor antagonist. Percent change in coronary artery diameter, coronary blood flow, and coronary vascular resistance were calculated on the basis of quantitative coronary angiography and intracoronary Doppler. At 12 weeks, total cholesterol was significantly and similarly increased in all groups. Chronic endothelin receptor antagonism significantly increased coronary blood flow in response to acetylcholine at 12 weeks (group 1: -41.6%+/-10.7%, group 2: -4.7%+/-11.9%, group 3: 11.4%+/-7.4%).


CONCLUSIONS
Chronic endothelin receptor antagonism preserves coronary endothelial function in experimental hypercholesterolemia. This study supports the role for ET-1 in the pathogenesis of endothelial function. Moreover, endothelin receptor antagonists may have a therapeutic role by maintaining coronary endothelial function in pathophysiological states.
Best
P J
PJ
Department of Internal Medicine, Division of Cardiovascular Diseases, Mayo Clinic and Mayo Foundation, Rochester, MN, USA.
McKenna
C J
CJ
Hasdai
D
D
Holmes
D R
DR
Lerman
A
A
D000284:Administration, Oral; D000818:Animals; D000077868:Atrasentan; D000077300:Bosentan; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D006439:Hemodynamics; D006937:Hypercholesterolemia / Q000097:blood / Q000503:physiopathology*; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology; D011897:Random Allocation; D044022:Receptor, Endothelin A; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology; D013552:Swine
D065128:Endothelin Receptor Antagonists; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; C118553:Ro 48-5695; D013449:Sulfonamides; D000077300:Bosentan; D000077868:Atrasentan