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Coronary endothelial function is preserved with chronic endothelin receptor antagonism in experimental
P J Best1, L O Lerman, J C Romero
1Department of Internal Medicine, Division of Cardiovascular Diseases, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA.
Insights
High cholesterol impairs blood vessel function by reducing nitric oxide (NO). Endothelin receptor antagonists improved NO levels and preserved endothelial function in pigs with hypercholesterolemia.
Area of Science:
- Cardiovascular Science
- Pharmacology
- Endocrinology
Background:
- Hypercholesterolemia is linked to elevated endothelin-1, reduced nitric oxide (NO) activity, and impaired endothelial function.
- Endothelin-1 plays a crucial role in regulating vascular tone and endothelial function.
Purpose of the Study:
- To investigate the hypothesis that chronic endothelin receptor antagonism can preserve endothelial function and enhance NO activity in a porcine model of hypercholesterolemia.
- To evaluate the efficacy of a combined endothelin receptor antagonist (RO-48-5695) and a selective endothelin-A receptor antagonist (ABT-627) in ameliorating hypercholesterolemia-induced vascular dysfunction.
Main Methods:
- Pigs were fed a high-cholesterol (HC) diet and randomized to receive either no treatment, RO-48-5695, or ABT-627 for 12 weeks.
- Coronary endothelial function was assessed by measuring bradykinin-induced relaxation.
- Plasma levels of nitric oxide metabolites (NOx) were quantified using chemiluminescence.
Main Results:
- Hypercholesterolemia significantly attenuated bradykinin-induced coronary relaxation compared to normal-diet controls.
- Endothelin receptor antagonism (both combined and selective) normalized coronary endothelial function.
- Plasma NOx levels decreased by 74.8% in the untreated HC group but were significantly attenuated by endothelin receptor antagonists (-28.2% and -38.9%).
Conclusions:
- Chronic endothelin receptor antagonism effectively preserves coronary endothelial function in the setting of hypercholesterolemia.
- Endothelin receptor antagonists increase NO activity and represent a potential therapeutic strategy for managing hypercholesterolemia-related cardiovascular complications.
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.