Effect of combination of calcium antagonist, azelnidipine, and AT1 receptor blocker, olmesartan, on atherosclerosis in apolipoprotein E-deficient mice.
OBJECTIVE
Angiotensin II type 1 receptor blockers (ARB) are widely recognized to have a vasculoprotective effect. Accumulating data have revealed that calcium antagonists also retard atherosclerosis. We examined the possibility that combination therapy of ARB and calcium antagonists could more effectively prevent atherosclerosis than monotherapy.


RESULTS
We observed a marked increase in the atherosclerotic area, associated with the exaggerated expression of nicotinamide adenine dinucleotide (phosphate), reduced form [NAD(P)H] oxidase subunits (p22 and p47) and superoxide anion production, in the aorta of apolipoprotein E-deficient mice maintained on a 1.25% high-cholesterol diet for 10 weeks. A calcium antagonist, azelnidipine, at a dose of 1 mg/kg a day or an ARB, olmesartan, at a dose of 3 mg/kg a day, significantly inhibited these parameters, with no change in systolic blood pressure and the blood cholesterol level. Moreover, the co-administration of lower doses of azelnidipine (0.1 mg/kg a day) and olmesartan (1 mg/kg a day) significantly inhibited the atherosclerotic area and oxidative stress, whereas azelnidipine or olmesartan alone at these doses did not affect these parameters. Furthermore, we observed similar inhibitory effects of azelnidipine or olmesartan on angiotensin II-induced NADPH oxidase activity and Akt activity in cultured vascular smooth muscle cells.


CONCLUSIONS
These results suggest that the co-administration of calcium antagonists and ARB synergistically blunts oxidative stress at least partly through the inhibition of Akt activity and enhances the beneficial effects of these drugs on atherosclerosis compared with monotherapy.
Suzuki
Jun
J
Department of Molecular and Cellular Biology, Division of Medical Biochemistry and Cardiovascular Biology, Ehime University School of Medicine, Ehime, Japan.
Iwai
Masaru
M
Li
Zhen
Z
Li
Jian-Mei
JM
Min
Li-Juan
LJ
Ide
Ayumi
A
Yoshii
Toyofumi
T
Oshita
Akira
A
Mogi
Masaki
M
Horiuchi
Masatsugu
M
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency*; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001383:Azetidinecarboxylic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D015153:Blotting, Western; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D004095:Dihydropyridines / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D019255:NADPH Oxidases / Q000378:metabolism; D000068557:Olmesartan Medoxomil; D018384:Oxidative Stress / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D013481:Superoxides / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D013997:Time Factors
D047228:Angiotensin II Type 1 Receptor Blockers; D001057:Apolipoproteins E; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D007093:Imidazoles; D011518:Proto-Oncogene Proteins; D013777:Tetrazoles; D013481:Superoxides; D001383:Azetidinecarboxylic Acid; D000068557:Olmesartan Medoxomil; D019255:NADPH Oxidases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C061679:azelnidipine