Pharmacological and pharmacokinetic study of olmesartan medoxomil in animal diabetic retinopathy models.
A close relationship between the renin-angiotensin system and the pathophysiology of diabetic retinopathy has been suggested, several angiotensin II type 1 receptor (angiotensin AT1 receptor) antagonists being effective in animal models. Therefore, we examined the efficacy of an angiotensin AT1 receptor antagonist, olmesartan medoxomil (CS-866), in animal retinopathy models. In diabetic stroke-prone spontaneously hypertensive (SHRSP) rats, 4-week treatment with CS-866 prevented the elongation of oscillatory potential peaks dose-dependently which almost normalized at 3 mg/kg/day. Next, in oxygen-induced retinopathy mice, CS-866 at 1 mg/kg significantly prevented the retinal neovascularization. In these animal models, plasma concentrations of CS-866 were comparable to the in vitro IC50 value of the angiotensin AT1 receptor. In summary, our data demonstrated that CS-866 was effective in early and late stage retinopathy models through the inhibition of the angiotensin AT1 receptor. These findings suggest the possibility of CS-866 as a therapeutic agent for diabetic retinopathy.
Nakamura
Hiroaki
H
Pharmacology and Molecular Biology Research Laboratories, Sankyo Co., Ltd., 2-58, Hiromachi 1-chome, Shinagawa-ku, Tokyo 140-8710, Japan. nakamura_hiroaki@sankyo.co.jp
Inoue
Tatsuya
T
Arakawa
Naohisa
N
Shimizu
Yuki
Y
Yoshigae
Yasushi
Y
Fujimori
Izumi
I
Shimakawa
Emi
E
Toyoshi
Tohru
T
Yokoyama
Tomihisa
T
D047228:Angiotensin II Type 1 Receptor Blockers / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D019540:Area Under Curve; D001562:Benzimidazoles / Q000493:pharmacokinetics / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000493:pharmacokinetics / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000503:physiopathology; D003930:Diabetic Retinopathy / Q000097:blood / Q000503:physiopathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004596:Electroretinography; D006442:Glycated Hemoglobin / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000150:complications / Q000503:physiopathology; D000860:Hypoxia / Q000503:physiopathology; D007093:Imidazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D000068557:Olmesartan Medoxomil; D010100:Oxygen / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D015861:Retinal Neovascularization / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D013777:Tetrazoles / Q000493:pharmacokinetics / Q000494:pharmacology*
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D001786:Blood Glucose; D006442:Glycated Hemoglobin; D007093:Imidazoles; D000068557:Olmesartan Medoxomil; D010100:Oxygen; D013777:Tetrazoles; C437965:olmesartan; C077793:candesartan cilexetil