DUAL EFFECTS OF DICHLOROACETATE ON CARDIAC ISCHEMIC PRECONDITIONING IN THE RAT ISOLATED-PERFUSED HEART

1 Ischaemic cardiac preconditioning represents an important cardioprot ective 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 ischaemi a) 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 al l. Throughout reperfusion mechanical performance was assessed as the r ate-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 (RPPt=60) was 4,246 +/- 974 mmHg beats min(-1) compared to baseline value of 21,297 +/- 1,728 mmHg beats min(-1)). Pr econditioning with either 3 x 4 min or 3 x 6 min cycles caused signifi cant protection, as shown by enhanced recovery (RPPt=60 = 7,818 +/- 1, 138, P < 0.05, and 11,123 +/- 587 mmHg beats min(-1), P < 0.001, respe ctively). 4 Addition of DCA (3 mM) to hearts under baseline conditions significantly (P < 0.001) enhanced systolic function with an increase d 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 e ffect on recovery of mechanical performance in the nonpreconditioned h earts (RPPt=60 = 3,640 +/- 1,235 mmHg beats min(-1)) while the benefic ial effects of preconditioning were reduced in the preconditioned hear ts (3 x 4 min: RPPt=60 = 2,919 +/- 1,060 mmHg beats min(-1); 3 x 6 min : RPPt=60 = 8,032 +/- 1,367 mmHg beats min(-1)). Therefore, DCA had in creased the threshold for preconditioning. 6 By contrast, post-treatme nt of hearts with 3 mM DCA substantially improved recovery on reperfus ion in all groups (RPPt=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 investigat ion clearly show that pretreatment with DCA enhances baseline cardiac mechanical performance but increases the threshold for cardiac precond itioning. However, post treatment with DCA substantially augments the beneficial effects of preconditioning.