Inhibitor for advanced glycation end products formation attenuates hypertension and oxidative damage in genetic hypertensive rats.
OBJECTIVE
A recent study demonstrated that free radicals were involved in the maintenance of hypertension in stroke-prone spontaneously hypertensive rats (SHRSP). Advanced glycation end-products (AGEs) accumulate progressively in the vasculature with ageing, and have been identified to be relevant mediators for various vascular complications. To elucidate the role of AGEs in genetic hypertension, we investigated the effect of OPB-9195, a novel inhibitor of AGEs, on hypertension and oxidative damage in SHRSP.


METHODS
Five-week-old male SHRSP were divided into a control group, fed a control diet and two, OPB-9195, (+/-)-2-isopropylidenehydrazono-4-oxo-thiazolidin-5-ylacetanilide, treatment groups, fed a diet supplemented with OPB-9195 at the concentration of 0.5 (OPB-L) or 2 mg/g (OPB-H) mixed chow for 10 weeks.


RESULTS
The plasma of OPB-9195-treated SHRSP had lower levels of glycated albumin as compared with that of control SHRSP. OPB-9195 lowered the systolic blood pressure (SBP) by the fourth week of administration, and this effect was maintained throughout the study. We also confirmed SBP and diastolic blood pressure (DBP) rhythms, monitored by telemetry, were significantly lower in the OPB-H group than in the control group. Urinary nitric oxide (NO) excretion as well as the expression of endothelial NO synthase (eNOS) mRNA, and eNOS activity in the aorta were significantly increased in OPB-9195-treated groups compared with the control group. The levels of 8-hydroxydeoxyguanosine (8-OHdG), produced from deoxyguanosine under conditions of oxidative stress, in the urine of OPB-9195-treated SHRSP was significantly lower than in the control SHRSP. We also confirmed that the expression of glutathione peroxidase in the aorta was significantly increased in OPB-9195 treated SHRSP.


CONCLUSIONS
Because long-term administration of a AGEs inhibitor reduces blood pressure and oxidative damage in SHRSP, this study suggests a role for AGEs in the progression or maintenance of hypertension and related diseases in genetic hypertension.
Mizutani
Ken-Ichi
K
Laboratory of Life Science, Graduate School of Human and Environmental Studies, Kyoto University, Kyoto, Japan. mizutani@frontier.kyoto-u.ac.jp
Ikeda
Katsumi
K
Tsuda
Kinsuke
K
Yamori
Yukio
Y
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002940:Circadian Rhythm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000652:urine; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D013830:Thiadiazoles / Q000494:pharmacology; D053778:Thiazolidines
D004791:Enzyme Inhibitors; D017127:Glycation End Products, Advanced; C105739:OPB 9195; D012333:RNA, Messenger; D013830:Thiadiazoles; D053778:Thiazolidines; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D019331:NG-Nitroarginine Methyl Ester