Pjm. Best et al., Coronary endothelial function is preserved with chronic endothelin receptor antagonism in experimental hypercholesterolemia in vitro, ART THROM V, 19(11), 1999, pp. 2769-2775
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.