Nifedipine prevents vascular endothelial dysfunction in a mouse model of obesity and type 2 diabetes, by improving eNOS dysfunction and dephosphorylation.
The effect of calcium channel blockers (CCBs) on type 2 diabetes is still unclear. The present study was undertaken to examine the efficacy of nifedipine, a dihydropyridine CCB, on obesity, glucose intolerance and vascular endothelial dysfunction in db/db mice (a mouse model of obesity and type 2 diabetes). db/db mice, fed high-fat diet (HFD) were treated with vehicle, nifedipine (10 mg kg(-1) day(-1)) or hydralazine (5 mg kg(-1) day(-1)) for 4 weeks, and the protective effects were compared. Although nifedipine and hydralazine exerted similar blood pressure lowering in db/db mice, neither affected body weight, fat weight, and glucose intolerance of db/db mice. However, nifedipine, but not hydralazine, significantly improved vascular endothelial function in db/db mice, being accompanied by more attenuation of vascular superoxide by nifedipine than hydralazine. These protective effects of nifedipine were attributed to the attenuation of eNOS uncoupling as shown by the prevention of vascular endothelial nitric oxide synthase (eNOS) dimer disruption, and the prevention of dihydrofolate reductase (DHFR) downregulation, the key enzyme responsible for eNOS uncoupling. Moreover, nifedipine, but not hydralazine, significantly prevented the decreases in phosphorylation of vascular akt and eNOS in db/db mice. Our work provided the first evidence that nifedipine prevents vascular endothelial dysfunction, through the inhibition of eNOS uncoupling and the enhancement of eNOS phosphorylation, independently of blood pressure-lowering effect. We propose that nifedipine may be a promising therapeutic agent for cardiovascular complications in type 2 diabetes.
Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjyo, Kumamoto 860-8556, Japan.
Eiichiro
E
Yamamoto
Taishi
T
Nakamura
Keiichiro
K
Kataoka
Yoshiko
Y
Tokutomi
Yi-Fei
YF
Dong
Masaya
M
Fukuda
Hisato
H
Nako
Osamu
O
Yasuda
Hisao
H
Ogawa
Shokei
S
Kim-Mitsuyama
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology*; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D005951:Glucose Tolerance Test; D051379:Mice; D008815:Mice, Inbred Strains; D009543:Nifedipine / Q000494:pharmacology*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D009765:Obesity / Q000201:enzymology*; D009929:Organ Size / Q000187:drug effects; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
D002121:Calcium Channel Blockers; D013481:Superoxides; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D009543:Nifedipine