Alagebrium in combination with exercise ameliorates age-associated ventricular and vascular stiffness

초록

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 +/- 0.4 mm Hg/mu L, P<0.05), dP/dt(max) was attenuated (6054 +/- 685 vs 9540 +/- 939 mm Hg/s, P<0.05), ventricular compliance (end-diastolic pressure-volume relationship (EDPVR)) was impaired (1.4 +/- 0.2 vs 0.5 +/- 0.4 mm Hg/mu L, P<0.05) and diastolic relaxation time (tau) was prolonged (21 +/- 3 vs 14 +/- 2 ms, P<0.05). In old rats, combined ALT + Ex (4 weeks) increased dP/dt(max) and Ees (8945 +/- 665 vs 6054 +/- 685 mm Hg/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 +/- 3 ms, 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 +/- 0.3 ms, 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 +/- 0.3 ms, 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. (C) 2012 Published by Elsevier Inc.

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