Additive beneficial effects of amlodipine and atorvastatin in reversing advanced cardiac hypertrophy in elderly spontaneously hypertensive rats.
1. Additive beneficial effects on cardiovascular disease have been reported for amlodipine and atorvastatin. However, it is still unclear whether the combination of amlodipine and atorvastatin has additive beneficial effects on the regression of advanced cardiac hypertrophy in hypertension. In the present study, the effects of the drug combination on advanced cardiac hypertrophy were investigated in elderly spontaneously hypertensive rats (SHR). 2. Elderly SHR (36 weeks old) were randomly allocated into four groups of 12: (i) a vehicle-treated control group; (ii) an amlodipine (10 mg/kg per day)-treated group; (iii) an atorvastatin (10 mg/kg per day)-treated group; and (iv) a group treated with a combination of amlodipine and atorvastatin (both at 10 mg/kg per day). Drugs were administered by oral gavage every morning for a period of 12 weeks before hearts were harvested for analysis. 3. Combined administration of amlodipine and atorvastatin significantly suppressed cardiomyocyte hypertrophy, interstitial fibrosis and upregulation of hypertrophic and profibrotic genes, and also improved left ventricular diastolic dysfunction to a greater extent than did amlodipine monotherapy. Further beneficial effects of combination therapy on advanced cardiac hypertrophy were associated with a greater reduction of NADPH oxidase-mediated increases in cardiac reactive oxygen species (ROS), rather than decreased blood pressure and serum cholesterol levels. 4. To elucidate the underlying molecular mechanisms, we examined cardiovascular NADPH oxidase subunits and found that amlodipine clearly attenuated the expression of p47(phox) and p40(phox) and slightly but significantly reduced p22(phox) and Rac-1 levels in heart tissue. Combination treatment with amlodipine plus atorvastatin led to a further reduction in p22(phox), p47(phox) and Rac-1 protein levels compared with amlodipine alone. 5. In conclusion, combined amlodipine and atorvastatin treatment has a greater beneficial effect on advanced cardiac hypertrophy compared with amlodipine monotherapy. The benefits are likely to be related to the additive effects of the drugs on the suppression of NADPH oxidase-mediated ROS generation.
Lu
Jing-Chao
JC
Department of Cardiology, Second Hospital of Hebei Medical University, Shijiazhuang City, Hebei, China.
Cui
Wei
W
Zhang
Hai-Lin
HL
Liu
Fan
F
Han
Mei
M
Liu
De-Min
DM
Yin
Hong-Ning
HN
Zhang
Kai
K
Du
Jun
J
D000375:Aging / Q000187:drug effects*; D017311:Amlodipine / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000069059:Atorvastatin; D006332:Cardiomegaly / Q000150:complications / Q000188:drug therapy*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005355:Fibrosis / Q000378:metabolism; D054144:Heart Failure, Diastolic / Q000150:complications / Q000188:drug therapy*; D006439:Hemodynamics / Q000187:drug effects; D006538:Heptanoic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D032383:Myocytes, Cardiac / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism; D020097:Natriuretic Peptide, Brain / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D011918:Rats, Inbred SHR; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000378:metabolism / Q000503:physiopathology
D000924:Anticholesteremic Agents; D000959:Antihypertensive Agents; D006538:Heptanoic Acids; D011758:Pyrroles; D017382:Reactive Oxygen Species; D020097:Natriuretic Peptide, Brain; D017311:Amlodipine; D000069059:Atorvastatin; D013482:Superoxide Dismutase; D019255:NADPH Oxidases