Effects of combined olmesartan and pravastatin on glucose intolerance and cardiovascular remodeling in a metabolic-syndrome model.
Hypertension and dyslipidemia frequently coexist in patients with progressive insulin resistance and thus constitute metabolic syndrome. We sought to determine the merits of combining an angiotensin II receptor blocker and a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor in treating this pathological condition. Five-week-old Otsuka Long-Evans Tokushima Fatty rats, a model of metabolic syndrome, were untreated or treated with olmesartan 3 mg kg(-1) per day, pravastatin 30 mg kg(-1) per day or their combination for 25 weeks. Long-Evans Tokushima Otsuka rats served as normal controls. The antihypertensive effect of olmesartan and the lipid-lowering properties of pravastatin were both augmented by the combination. The oral glucose tolerance test revealed that only the combined treatment significantly reduced the area under the time-glucose curve, which was accompanied by augmented adiponectin messenger RNA expression in epididymal adipose tissue. Although the total cardiac endothelial nitric oxide synthetase (eNOS) content did not significantly differ among the groups, the combined treatment significantly increased the content of dihydrofolate reductase, a key eNOS coupler. Dihydroethidium staining of the aorta showed that the combination most significantly attenuated superoxide production. Moreover, Azan-Mallory staining revealed that the combination most significantly limited the perivascular fibrosis and wall thickening of intramyocardial coronary arteries. In conclusion, the combination of olmesartan and pravastatin augmented adiponectin expression in white adipose tissue and improved glucose tolerance in a rat model of metabolic syndrome, which was associated with more significant ameliorations of cardiovascular redox state and remodeling than those by treatments with either agent alone.
Mizukawa
Mizuki
M
Department of Cardiorenal Cerebrovascular Medicine, Kagawa University Faculty of Medicine, Kagawa, Japan.
Ohmori
Koji
K
Obayashi
Ayumi
A
Ishihara
Yasuhiro
Y
Yoshida
Junji
J
Noma
Takahisa
T
Yukiiri
Kazushi
K
Kosaka
Hiroaki
H
Kohno
Masakazu
M
D052242:Adiponectin / Q000096:biosynthesis; D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D002319:Cardiovascular System / Q000473:pathology*; D004359:Drug Therapy, Combination; D004435:Eating / Q000187:drug effects; D018149:Glucose Intolerance / Q000188:drug therapy*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007093:Imidazoles / Q000627:therapeutic use*; D008055:Lipids / Q000097:blood; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy* / Q000473:pathology*; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis; D010084:Oxidation-Reduction; D017035:Pravastatin / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D020334:Rats, Inbred OLETF; D013481:Superoxides / Q000378:metabolism; D013762:Tetrahydrofolate Dehydrogenase / Q000096:biosynthesis; D013777:Tetrazoles / Q000627:therapeutic use*
D052242:Adiponectin; D047228:Angiotensin II Type 1 Receptor Blockers; D001786:Blood Glucose; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007093:Imidazoles; D008055:Lipids; D012333:RNA, Messenger; D013777:Tetrazoles; D013481:Superoxides; C437965:olmesartan; D052250:Nitric Oxide Synthase Type III; D013762:Tetrahydrofolate Dehydrogenase; D017035:Pravastatin