Efficacy of olmesartan and nifedipine on recurrent hypoxia-induced left ventricular remodeling in diabetic mice.
OBJECTIVE
Recurrent hypoxia due to sleep apnea syndrome is implicated in cardiovascular events, especially in diabetic patients, but the underlying mechanisms remain controversial. We previously reported that angiotensin II receptor blockers can improve hypoxia-induced left ventricular remodeling. The aim of this study was to examine the effect on left ventricular remodeling of adding a calcium channel blocker to angiotensin II receptor blocker therapy in diabetic mice exposed to recurrent hypoxia.


METHODS
Male db/db mice (8-week-old) and age-matched control db/+ mice were fed a Western diet and subjected to recurrent hypoxia (oxygen at 10+/-0.5% for 8h daily during the daytime) or normoxia for 3weeks. Hypoxic db/db mice were treated with the vehicle, olmesartan (3mg/kg/day), nifedipine (10mg/kg/day), or both drugs.


RESULTS
Recurrent hypoxia caused hypertrophy of cardiomyocytes, interstitial fibrosis, and a significant increase in expression of the oxidative stress marker 4-hydroxy-2-nonenal (4-HNE) in the left ventricular myocardium. Treatment with olmesartan, nifedipine, or both drugs had no effect on systolic blood pressure, and each treatment achieved similar suppression of 4-HNE expression. Olmesartan and the combination with olmesartan and nifedipine significantly prevented cardiomyocyte hypertrophy more than treatment with nifedipine alone. On the other hand, olmesartan combined with nifedipine significantly reduced cytokine expression, superoxide production and matrix metalloproteinase (MMP)-9 activity, and significantly suppressed interstitial fibrosis in the left ventricular myocardium.


CONCLUSIONS
The combination with olmesartan and nifedipine, as well as a monotherapy with olmesartan, exerts preferable cardioprotection in diabetic mice exposed to recurrent hypoxia.
Yamashita
Chika
C
Laboratory of Pathological and Molecular Pharmacology, Osaka University of Pharmaceutical Sciences, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan.
Hayashi
Tetsuya
T
Mori
Tatsuhiko
T
Matsumoto
Chika
C
Kitada
Kento
K
Miyamura
Masatoshi
M
Sohmiya
Koichi
K
Ukimura
Akira
A
Okada
Yoshikatsu
Y
Yoshioka
Toshitaka
T
Kitaura
Yasushi
Y
Matsumura
Yasuo
Y
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D004041:Dietary Fats / Q000009:adverse effects; D004359:Drug Therapy, Combination; D000860:Hypoxia / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control; D007093:Imidazoles / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008820:Mice, Obese; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D009543:Nifedipine / Q000008:administration & dosage*; D055502:Secondary Prevention; D013777:Tetrazoles / Q000008:administration & dosage*; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology
D004041:Dietary Fats; D007093:Imidazoles; D013777:Tetrazoles; C437965:olmesartan; D009543:Nifedipine