Effect of combined treatment with an angiotensin II receptor antagonist and an HMG-CoA reductase inhibitor on atherosclerosis in genetically hyperlipidemic rabbits.
The purpose of this study was to examine whether coadministration of olmesartan medoxomil (OLM), an AT1 subtype specific angiotensin II receptor blocker (ARB), and pravastatin (PRV), a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, could enhance the antiatherogenic effect compared with monotherapy. Vehicle, PRV (25 mg/kg), OLM (0.5 mg/kg), and PRV (25 mg/kg) and OLM (0.5 mg/kg) in combination were administered to Watanabe heritable hyperlipidemic (WHHL) rabbits for 8 months. OLM alone and in combination lowered blood pressure to a similar degree, whereas PRV alone had no effect. PRV alone and in combination lowered blood cholesterol to a similar degree, whereas OLM alone had no effect. The combination of PRV and OLM decreased effectively both surface lesion area and lesional thickness in aortic tissue, producing a greater reduction in aortic cholesterol content than either drug alone. Immunohistological examination of the aorta revealed that PRV reduced macrophage infiltration and lipid deposition and that OLM reduced macrophage infiltration accompanied by reduction in monocyte chemoattractant protein-1 expression and N-(carboxymethyl)lysine protein adduct, an oxidative stress marker. It is concluded that OLM, an ARB, and PRV, an HMG-CoA reductase inhibitor, in combination produce a greater antiatherogenic effect than monotherapy via the combination of the different antiatherosclerotic mechanisms of each drug.
Kato
Mikio
M
Pharmacology and Molecular Biology Research Laboratories, Sankyo Company, Limited, Tokyo, Japan.
Sada
Toshio
T
Mizuno
Makoto
M
Kitayama
Ken
K
Inaba
Toshimori
T
Koike
Hiroyuki
H
D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects; D018932:Chemokine CCL2 / Q000097:blood; D002784:Cholesterol / Q000097:blood; D004359:Drug Therapy, Combination; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006949:Hyperlipidemias / Q000188:drug therapy* / Q000235:genetics; D007093:Imidazoles / Q000627:therapeutic use; D007150:Immunohistochemistry; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000068557:Olmesartan Medoxomil; D017035:Pravastatin / Q000627:therapeutic use; D011817:Rabbits; D013777:Tetrazoles / Q000627:therapeutic use; D017539:Tunica Intima / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D047228:Angiotensin II Type 1 Receptor Blockers; D018932:Chemokine CCL2; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007093:Imidazoles; D013777:Tetrazoles; D000068557:Olmesartan Medoxomil; D002784:Cholesterol; D017035:Pravastatin