Amitriptyline pharmacologically preconditions rat hearts against cardiac ischemic-reperfusion injury

Background/objectives: Amitriptyline (AMY) is a tricyclic anti-depressant that has recently been shown to have anti-inflammatory properties. We investigated whether AMY is cardioprotective against reperfusion injury in ex-vivo rat hearts. Methods: Thirty adult Sprague-Dawley rat hearts were perfused ex-vivo in a Langendorff apparatus. All hearts except SHAM (n=6, perfused for 110 min.) received 30 min no-flow ischemia followed by 40 min reperfusion (I-R). One group (n=6) was untreated before I-R (non-preconditioned; NPC), another non-preconditioned group was perfused with 10 mu M amitriptyline for 30 min before I-R (NPC-AMY, n=6). One group was preconditioned with 3 x 5-minute periods of ischemia before I-R (PC, n=6) and a fifth group was preconditioned in the presence of 10 mu M amitriptyline (PC-AMY, n=6). p38 phosphorylation and HMGB1 levels were quantified using Western blots. Data was analysed using multiway ANOVAs with Tukey HSD and linear regression models with Sobel mediator tests. Results: NPC hearts recovered poorly (LVDP recovered to 26.5 +/- 10.5% of pre-ischemic values, compared to PC hearts (82.8 +/- 14.9%: P < 0.05)). PC-AMY (69.9 +/- 6.16%) and NPC-AMY (90.3 +/- 10.0%) groups both recovered well (P < 0.05). The Sobel mediator test suggested that p38 activity may be indirectly involved in the amitriptyline induced cardioprotection (P < 0.05). HMGB1 was lower in amitriptyline treated hearts compared to the non-preconditioned hearts (P < 0.05) but the multiway ANOVA test suggests that HMGB1 was not involved in amitriptyline induced protection. Conclusions: Amitriptyline at 10 mu M protects hearts against ischemic-reperfusion injury which may be partially mediated through p38 phosphorylation. Crown Copyright (C) 2015 Published by Elsevier Ireland Ltd. All rights reserved.