Atorvastatin, a
hydroxymethylglutaryl-CoA reductase inhibitor, and
endothelin-1 (ET-1) receptor antagonist have been separately indicated to ameliorate
disease progression in
atherosclerosis. However, no study has evaluated the effect of their combination on
atherosclerosis. The objective of the current study was to evaluate the direct in vivo effects of a combination regimen of
atorvastatin and ET-1 receptor antagonist on male New Zealand white rabbit models of
atherosclerosis (injury-induced). Thirty-two atherosclerotic rabbits were divided into four experimental groups: (a) injury group - fed high-fat diet; (b) ET-1 receptor antagonist preventive group - fed high-fat diet, but with intragastric administration of the ET-1 receptor antagonist,
darusentan; (c) combined preventive group - fed high-fat diet, but with intragastric administration of both
darusentan and
atorvastatin; and (d) treatment group - fed high-fat diet for the first 8 weeks, followed by normal diet and intragastric administration of both
darusentan and
atorvastatin up to 16 weeks. A further eight non-atherosclerotic rabbits were fed normal diet and classified as the control group. At the end of 8 and 16 weeks, compared with the injury group, the combined preventive group had significant reduction in both the concentration of serum
lipids and inflammatory factors and
atherosclerosis formation, indicative of a multifaceted anti-atherosclerotic impact. The relative area of atherosclerotic lesions in the injury group (30.84%) was significantly higher than the control group (4.62%; p < 0.05). The combined preventive group showed a significantly robust effect on lowering serum
lipid, inflammatory
cytokines, and maintained homeostatic balance of
free radicals, and important downstream effectors like ET-1 and matrixmetalloproteinase-9. Our data show that
atorvastatin and ET-1 receptor antagonist co-administration may decrease
lipid levels, stabilize plaques and relieve vascular
inflammation. By reducing the plaque burden, this regimen may minimize the risk of
atherosclerotic plaque rupture or
arterial occlusion.