title: Alagebrium in combination with exercise ameliorates age-associated ventricular and vascular stiffness.
abstract: Advanced glycation end-products (AGEs) initiate cellular inflammation and contribute to cardiovascular disease in the elderly. AGE can be inhibited by Alagebrium (ALT), an AGE cross-link breaker. Moreover, the beneficial effects of exercise on aging are well recognized. Thus, we investigated the effects of ALT and exercise (Ex) on cardiovascular function in a rat aging model. Compared to young (Y) rats, in sedentary old (O) rats, end-systolic elastance (Ees) decreased (0.9±0.2 vs 1.7±0.4mmHg/μL, P<0.05), dP/dt(max) was attenuated (6054±685 vs 9540±939mmHg/s, P<0.05), ventricular compliance (end-diastolic pressure-volume relationship (EDPVR)) was impaired (1.4±0.2 vs 0.5±0.4mmHg/μL, P<0.05) and diastolic relaxation time (tau) was prolonged (21±3 vs 14±2ms, P<0.05). In old rats, combined ALT+Ex (4weeks) increased dP/dt(max) and Ees (8945±665 vs 6054±685mmHg/s, and 1.5±0.2 vs 0.9±0.2 respectively, O with ALT+Ex vs O, P<0.05 for both). Diastolic function (exponential power of EDPVR and tau) was also substantially improved by treatment with Alt+Ex in old rats (0.4±0.1 vs 0.9±0.2 and 16±2 vs 21±3ms, respectively, O with ALT+EX vs O, P<0.05 for both). Pulse wave velocity (PWV) was increased in old rats (7.0±0.7 vs 3.8±0.3ms, O vs Y, P<0.01). Both ALT and Ex alone decreased PWV in old rats but the combination decreased PWV to levels observed in young (4.6±0.5 vs 3.8±0.3ms, O with ALT+Ex vs Y, NS). These results suggest that prevention of the formation of new AGEs (with exercise) and breakdown of already formed AGEs (with ALT) may represent a therapeutic strategy for age-related ventricular and vascular stiffness.
authors.affiliation: Department of Anesthesiology & Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA.
authors.forename: Jochen
authors.initials: J
authors.lastname: Steppan
authors.forename: Huang
authors.initials: H
authors.lastname: Tran
authors.forename: Alexandre M
authors.initials: AM
authors.lastname: Benjo
authors.forename: Laxsmi
authors.initials: L
authors.lastname: Pellakuru
authors.forename: Viachaslau
authors.initials: V
authors.lastname: Barodka
authors.forename: Sungwoo
authors.initials: S
authors.lastname: Ryoo
authors.forename: Sineád M
authors.initials: SM
authors.lastname: Nyhan
authors.forename: Craig
authors.initials: C
authors.lastname: Lussman
authors.forename: Gaurav
authors.initials: G
authors.lastname: Gupta
authors.forename: Anthony R
authors.initials: AR
authors.lastname: White
authors.forename: Joao P
authors.initials: JP
authors.lastname: Daher
authors.forename: Artin A
authors.initials: AA
authors.lastname: Shoukas
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Levine
authors.forename: Dan E
authors.initials: DE
authors.lastname: Berkowitz
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D003971:Diastole / Q000502:physiology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors / Q000378:metabolism; D006439:Hemodynamics / Q000502:physiology; D008297:Male; D010805:Physical Conditioning, Animal / Q000502:physiology*; D051381:Rats; D011916:Rats, Inbred F344; D013599:Systole / Q000502:physiology; D013844:Thiazoles / Q000494:pharmacology*; D059289:Vascular Stiffness / Q000187:drug effects / Q000502:physiology*; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology*
chemical_list: D017127:Glycation End Products, Advanced; D013844:Thiazoles; C406794:alagebrium