Coronary endothelial function is preserved with chronic endothelin receptor antagonism in experimental hypercholesterolemia in vitro

Hypercholesterolemia is associated with increased circulating and tissue en dothelin-1 immunoreactivity, decreased nitric oxide (NO) activity, and alte red endothelial function. We tested the hypothesis that chronic endothelin receptor antagonism preserves endothelial function and increases NO in expe rimental porcine hypercholesterolemia. Pigs were randomized to 3 groups: Gr oup 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 b y a dose-response relaxation to bradykinin (10(-11) to 10(-6) mol/L), in al l groups ana in pigs maintained on a normal diet. Plasma total oxidized pro ducts of NO (NOx) were determined by chemiluminescence at baseline and afte r 12 weeks. Bradykinin-stimulated coronary epicardial and arteriolar relaxa tion in group 1 was attenuated compared with normal-diet controls, This rel axation was normalized with endothelin receptor antagonism. Plasma NOx decr eased after 12 weeks in group 1 (-74.8+/-5.5%). This decrease was attenuate d in the endothelin receptor antagonist groups (group 2, -28.2+/-15.0%; gro up 3, -38.9+/-20.6%). Chronic endothelin receptor antagonism preserves coro nary endothelial function and increases NO in hypercholesterolemia. This st udy supports a role of endothelin-1 in the regulation of NO activity and su ggests a possible therapeutic role for endothelin receptor antagonists in h ypercholesterolemia.