Dual effects of dichloroacetate on cardiac ischaemic preconditioning in the rat isolated perfused heart.
1. Ischaemic cardiac preconditioning represents an important cardioprotective mechanism which limits myocardial ischaemic damage. The aim of this investigation was to assess the impact of dichloroacetate (DCA), a pyruvate dehydrogenase complex activator, on preconditioning. 2. Rat isolated hearts were perfused by use of the Langendorff technique, and were subjected to either preconditioning (3 x 4 or 3 x 6 min ischaemia) or continuous perfusion, followed by 30 min global ischaemia and 60 min reperfusion. DCA (3 mM) was either given throughout the protocol (pretreatment), during reperfusion only (post-treatment), or not at all. Throughout reperfusion mechanical performance was assessed as the rate-pressure product (RPP: left ventricular developed pressure x heart rate). 3. In non-preconditioned control hearts, mechanical performance was substantially (P < 0.001) depressed on reperfusion (the RPP after 60 min of reperfusion (RPP(t=60)) was 4,246+/-974 mmHg beats min(-1) compared to baseline value of 21,297+/-1,728 mmHg beats min(-1)). Preconditioning with either 3 x 4 min or 3 x 6 min cycles caused significant protection, as shown by enhanced recovery (RPP(t=60) = 7,818+/-1,138, P < 0.05, and 11,123+/-587 mmHg beats min(-1), P < 0.001, respectively). 4. Addition of DCA (3 mM) to hearts under baseline conditions significantly (P < 0.001) enhanced systolic function with an increased left ventricular developed pressure of 108+/-5 mmHg compared to 88.3+/-3.0 mmHg in the controls. 5. Pretreatment with 3 mM DCA had no effect on recovery of mechanical performance in the non-preconditioned hearts (RPP(t=60) = 3,640+/-1,235 mmHg beats min(-1)) while the beneficial effects of preconditioning were reduced in the preconditioned hearts (3 x 4 min: RPP(t=60) = 2,919+/-1,060 mmHg beats min(-1); 3 x 6 min: RPP(t=60) = 8,032+/-1,367 mmHg beats min(-1)). Therefore, DCA had increased the threshold for preconditioning. 6. By contrast, post-treatment of hearts with 3 mM DCA substantially improved recovery on reperfusion in all groups (RPP(t=60) = 5,827+/-1,328 (non-preconditioned), 14,022+/-3,743 (3 x 4 min; P < 0.01) and 23,219+/-1,374 (3 x 6 min; P < 0.001) mmHg beats min(-1)). 7. The results of the present investigation clearly show that pretreatment with DCA enhances baseline cardiac mechanical performance but increases the threshold for cardiac preconditioning. However, post-treatment with DCA substantially augments the beneficial effects of preconditioning.
Randall
M D
MD
School of Biomedical Sciences, University of Nottingham Medical School.
Keon
C A
CA
Greenhaff
P L
PL
Constantin-Teodosiu
D
D
D000818:Animals; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D004734:Energy Metabolism; D004789:Enzyme Activation; D066298:In Vitro Techniques; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D017202:Myocardial Ischemia / Q000201:enzymology; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D011768:Pyruvate Dehydrogenase Complex; D003999:Dichloroacetic Acid