Amitriptyline pharmacologically preconditions rat hearts against cardiac ischemic-reperfusion injury.
OBJECTIVE
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 μM amitriptyline for 30 min before I-R (NPC-AMY, n = 6). One group was preconditioned with 3 × 5-minute periods of ischemia before I-R (PC, n = 6) and a fifth group was preconditioned in the presence of 10 μM 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 μM protects hearts against ischemic-reperfusion injury which may be partially mediated through p38 phosphorylation.
School of Medical Sciences, University of Adelaide, Adelaide, SA, Australia. Electronic address: sam.lee@adelaide.edu.au.
S M
SM
Lee
School of Medical Sciences, University of Adelaide, Adelaide, SA, Australia.
M
M
Hutchinson
School of Medical Sciences, University of Adelaide, Adelaide, SA, Australia.
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V
Staikopoulos
School of Medical Sciences, University of Adelaide, Adelaide, SA, Australia.
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DA
Saint
D000639:Amitriptyline / Q000008:administration & dosage*; D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage*; D006321:Heart / Q000187:drug effects*; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control*; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley
D002316:Cardiotonic Agents; D000639:Amitriptyline
Cardioprotection; Ischemia–reperfusion; Preconditioning; Reperfusion injury; Tricyclic-anti-depressant