November 1, 1999Open Access
View Full PaperCoronary Endothelial Function Is Preserved With Chronic Endothelin Receptor Antagonism in Experimental Hypercholesterolemia In Vitro
Key Result
Chronic endothelin receptor antagonism attenuated the decrease in plasma NOx (-28.2% and -38.9% vs -74.8%) and preserved coronary endothelial function in experimental porcine hypercholesterolemia.
Study Design
Type
RCT (n=23)
Randomization
Randomized to 3 groups
Structured PICO
Does chronic endothelin receptor antagonism preserve coronary endothelial function and increase nitric oxide in experimental porcine hypercholesterolemia?
P
Population
Pigs with experimental hypercholesterolemia induced by a 2% high-cholesterol diet (n=23) and normal-diet controls
I
Intervention
RO-48-5695 (combined endothelin receptor antagonist) or ABT-627 (selective endothelin-A receptor antagonist) added to a high-cholesterol diet for 12 weeks
C
Comparator
2% high-cholesterol diet alone and normal-diet controls
O
Outcome
Coronary epicardial and arteriolar endothelial function (dose-response relaxation to bradykinin) and plasma total oxidized products of NO (NOx) at 12 weekssurrogate
Chronic endothelin receptor antagonism preserves coronary endothelial function and nitric oxide activity in a porcine model of hypercholesterolemia.
Main Result
Absolute Event Rate: -28.2% vs -74.8%
Abstract
Hypercholesterolemia is associated with increased circulating and tissue endothelin-1 immunoreactivity, decreased nitric oxide (NO) activity, and altered endothelial function. We tested the hypothesis that chronic endothelin receptor antagonism preserves endothelial function and increases NO in experimental porcine hypercholesterolemia. Pigs were randomized to 3 groups: Group 1, a 2% high-cholesterol (HC) diet alone (n=7); group 2, RO-48-5695, a combined endothelin receptor antagonist, and an HC diet (n=8); and group 3, ABT-627, a selective endothelin-A receptor antagonist, and an HC diet (n=8). Coronary epicardial and arteriolar endothelial function was determined by a dose-response relaxation to bradykinin (10(-11) to 10(-6) mol/L), in all groups and in pigs maintained on a normal diet. Plasma total oxidized products of NO (NO(x)) were determined by chemiluminescence at baseline and after 12 weeks. Bradykinin-stimulated coronary epicardial and arteriolar relaxation in group 1 was attenuated compared with normal-diet controls. This relaxation was normalized with endothelin receptor antagonism. Plasma NO(x) decreased after 12 weeks in group 1 (-74.8+/-5.5%). This decrease was attenuated in the endothelin receptor antagonist groups (group 2, -28.2+/-15.0%; group 3, -38.9+/-20.6%). Chronic endothelin receptor antagonism preserves coronary endothelial function and increases NO in hypercholesterolemia. This study supports a role of endothelin-1 in the regulation of NO activity and suggests a possible therapeutic role for endothelin receptor antagonists in hypercholesterolemia.