C16, a novel advanced glycation endproduct breaker, restores cardiovascular dysfunction in experimental diabetic rats.
OBJECTIVE
Advanced glycation endproducts (AGE) have been implicated in the pathogenesis of diabetic complications, including diabetic cardiovascular dysfunction. 3-[2-(4-Bromo-phenyl)-1-methyl-2-oxo-ethyl]-4,5,6,7-tetrahydro-benzothiazol-3-ium bromide (C16), a novel AGE breaker, was investigated for its effects on the development of cardiovascular disease in diabetic rats.


METHODS
Rats that had streptozotocin-induced diabetes for 12 weeks were divided into groups receiving C16 or vehicle by gavage.


RESULTS
In hemodynamic studies of the left ventricle, C16 treatment (25 or 50 mg/kg) for 4 weeks resulted in a significant increase in left ventricular systolic pressure, +dp/dt(max), and -dp/dt(max) as compared with vehicle-treated diabetic rats. Furthermore, in hemodynamic studies of the cardiovascular system, C16 (12.5, 25, or 50 mg/kg) treatment for 4 weeks resulted in a dose-dependent and significant increase in cardiac output, a reduction of total peripheral resistance, and an increase in systemic arterial compliance when compared with vehicle-treated diabetic rats. Biochemical studies showed that C16 treatment also resulted in a significant decrease in immunoglobulin G-red blood cell surface crosslink content and an increase in collagen solubility. Morphological and immunohistochemical examinations indicated that C16 was able to prevent increases of the collagen type III/I ratio in the aorta and decrease the accumulation of AGE in the aorta.


CONCLUSIONS
C16 has the ability to reduce AGE accumulation in tissues in vivo, and can restore diabetes-associated cardiovascular disorders in rats. This provides a potential therapeutic approach for cardiovascular disease associated with diabetes and aging in humans.
Cheng
Gang
G
Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
Wang
Li-Li
LL
Qu
Wen-Sheng
WS
Long
Long
L
Cui
Hao
H
Liu
Hong-Ying
HY
Cao
Ying-Lin
YL
Li
Song
S
D000818:Animals; D001011:Aorta / Q000378:metabolism; D052160:Benzothiazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D002318:Cardiovascular Diseases / Q000378:metabolism / Q000503:physiopathology*; D024042:Collagen Type I / Q000378:metabolism; D024061:Collagen Type III / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors*; D006352:Heart Ventricles / Q000503:physiopathology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D014655:Vascular Resistance / Q000187:drug effects
C522432:3-(2-(4-bromophenyl)-1-methyl-2-oxoethyl)-4,5,6,7-tetrahydrobenzothiazol-3-ium; D052160:Benzothiazoles; D024042:Collagen Type I; D024061:Collagen Type III; D017127:Glycation End Products, Advanced