Synergistic neuroprotective effects of combined treatment with olmesartan plus azelnidipine in stroke-prone spontaneously hypertensive rats.
An angiotensin 2 type 1 receptor blocker, olmesartan, and a calcium channel blocker, azelnidipine, possess not only an antihypertensive effect but also an antioxidative effect and other beneficial effects. In the present study, we examined the efficacy of olmesartan and azelnidipine monotherapy (2 mg/kg or 10 mg/kg each) and their combination therapy (1 mg/kg each) on stroke-prone spontaneously hypertensive rats (SHR-SP) in relation to oxidative stress, inflammation, and the neurovascular unit. In comparison with the vehicle group, body weight, regional cerebral blood flow, and motor function were preserved, whereas systolic blood pressure and diastolic blood pressure decreased in the five drug-treatment groups. Spontaneous infarct volume decreased with the low-dose combination of olmesartan plus azelnidipine and with the high-dose olmesartan, with a further decrease in the high-dose azelnidipine group. In addition, these drugs dose-dependently reduced oxidative stresses, proinflammatory molecules, and well-preserved components of the neurovascular unit. The low-dose combination of olmesartan plus azelnidipine showed a better effect than the low-dose olmesartan or azelnidipine monotherapy. The present study shows that the low-dose combination of olmesartan plus azelnidipine demonstrates a greater synergistic benefit than monotherapy with a low-dose of olmesartan or azelnidipine in SHR-SP for preventing spontaneous infarct volume, reducing oxidative stresses and proinflammatory molecules, and imparting neurovascular protection. In addition, a high-dose of olmesartan showed a greater benefit without the lowering of blood pressure, probably because of the antioxidative and anti-inflammatory effects. A high dose of azelnidipine showed the best benefit, probably because of the two effects mentioned above related to the lowering of blood pressure.
Department of Neurology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Shikatacho, Okayama, Japan.
Yoshio
Y
Omote
Kentaro
K
Deguchi
Syoichiro
S
Kono
Wentao
W
Liu
Tomoko
T
Kurata
Nozomi
N
Hishikawa
Toru
T
Yamashita
Yoshio
Y
Ikeda
Koji
K
Abe
D000367:Age Factors; D000818:Animals; D001383:Azetidinecarboxylic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D001930:Brain Injuries / Q000175:diagnosis / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D018932:Chemokine CCL2 / Q000378:metabolism; D024141:Collagen Type IV / Q000378:metabolism; D004095:Dihydropyridines / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006339:Heart Rate / Q000187:drug effects; D007093:Imidazoles / Q000627:therapeutic use*; D017078:Laser-Doppler Flowmetry; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D011918:Rats, Inbred SHR; D020521:Stroke / Q000188:drug therapy* / Q000235:genetics; D013777:Tetrazoles / Q000627:therapeutic use*
C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D024141:Collagen Type IV; D004095:Dihydropyridines; D007093:Imidazoles; D013777:Tetrazoles; D001383:Azetidinecarboxylic Acid; C437965:olmesartan; D020780:Matrix Metalloproteinase 9; C061679:azelnidipine
SHR-SP; azelnidipine; neurovascular unit; olmesartan; oxidative stress