Treatment with endothelin-receptor antagonists increases NOS activity in hypercholesterolemia

Area of Science:

• Cardiovascular Science
• Endocrinology
• Pharmacology

Background:

• Hypercholesterolemia impairs endothelium-dependent relaxations and reduces nitric oxide (NO) synthase (NOS) activity.
• Systemic NO levels decrease, while endothelin-1 (ET-1) levels increase in hypercholesterolemia.
• ET-receptor antagonists improve NO levels and vascular function in hypercholesterolemic models.

Purpose of the Study:

• To investigate if chronic ET-receptor antagonist administration increases NO production via enhanced NOS activity in hypercholesterolemic pigs.
• To test the hypothesis that ET-receptor blockade elevates NO through increased NOS activity.

Main Methods:

• Hypercholesterolemic pigs were treated for 12 weeks with either a selective ET(A)-receptor antagonist (ABT-624) or a combined ET(A) + ET(B)-receptor antagonist (RO-48-5695).
• Endothelial cells from the thoracic aorta were analyzed for eNOS mRNA and eNOS activity.
• Systemic levels of NO metabolites (NOx) and ET-1 were measured.

Main Results:

• All groups showed increased total cholesterol, LDL cholesterol, and ET-1 levels.
• Circulating NOx levels increased following ET-receptor blockade.
• Total and Ca-dependent NOS activity was significantly higher in pigs treated with the combined ET(A) + ET(B) antagonist compared to the ET(A) antagonist alone.

Conclusions:

• Chronic combined ET(A) + ET(B) receptor antagonism in hypercholesterolemia increases NO production.
• The observed increase in systemic NOx levels may stem from posttranscriptional modifications of NOS.
• This suggests a potential therapeutic mechanism for ET-receptor antagonists in managing hypercholesterolemia-related vascular dysfunction.