Uncoupling of contractile function from mitochondrial tricarboxylic
acid cycle activity and oxygen consumption during reperfusion of
ischemic rat hearts.
Liu, Bin, Zainab El-Alaoui Talibi, Alexander S. Clanachan, Richard
Schulz, and Gary D. Lopaschuk.
Cardiovascular Disease Research Group, Departments of Pediatrics
and Pharmacology, The University of Alberta, Edmonton, Canada
APStracts 2:0280H, 1995.
Mechanical function during reperfusion of ischemic hearts perfused
with high levels of fatty acids recovers to a lesser extent than the
recovery of myocardial O2 consumption (MVO2). Whether contractile
function becomes uncoupled from mitochondrial tricarboxylic acid
cycle activity and mitochondrial respiration, or whether
mitochondrial ATP production is not efficiently used for contractile
activity, has not been determined. We measured the time course of
recovery of mechanical function, MVO2, and the pathways involved in
producing NADH and FADH2 for mitochondrial oxidative phosphorylation
in rat hearts reperfused for 60 min following a 30 min period of
global ischemia. Isolated working hearts were perfused with Krebs
-Henseleit buffer supplemented with a level of fatty acids that is
observed in the blood during a myocardial infarction or cardiac
surgery in man (1.2 mM palmitate bound to 3% albumin) and which also
contained 11 mM glucose, 2.5 mM Ca2+, and 100 [mu]U/ml insulin.
Hearts were perfused at an 11.5 mmHg left atrial preload and 80 mmHg
aortic afterload with either: a) glucose double-labeled with [5-3H]
and [U-14C] for measurement of glycolysis and glucose oxidation,
respectively, or b) palmitate labeled with [9,10-3H] for the
measurement of fatty acid oxidation. Following ischemia, hearts
recovered 26.5 +/- 5.4% (n = 29) of pre-ischemic mechanical function
over the 60 min reperfusion period. Although contractile function was
depressed during reperfusion, tricarboxylic acid (TCA) cycle
activity, fatty acid [beta]-oxidation, glucose oxidation, glycolysis,
and MVO2 rapidly recovered within 10 min of reperfusion. The degree
of recovery of these parameters all exceeded the degree of recovery
of mechanical function. Over 90% of the acetyl CoA entering the TCA
cycle was derived from fatty acid [beta]-oxidation, with glucose
oxidation providing the remainder. The efficiency of coupling between
LV work and mitochondrial TCA cycle activity and of LV work to
mitochondrial respiration decreased during reperfusion (to 33% and
37% of pre-ischemic levels). In contrast, coupling of TCA cycle
activity to MVO2 was similar during both the reperfusion and pre
-ischemic periods. Addition of dichloroacetate (DCA, 1 mM) during
reperfusion of ischemic hearts resulted in a significant increase in
both cardiac work and cardiac efficiency during reperfusion. The
beneficial effect of DCA was associated with a significant decrease
in H+ production due to an improved balance between glycolysis and
glucose oxidation. These data demonstrate that mitochondrial function
and overall myocardial ATP production quickly recover in rat hearts
reperfused following a transient period of global ischemia with high
levels of fatty acids. However, mitochondrial ATP production derived
from glucose and fatty acid metabolism is not efficiently translated
into mechanical work during reperfusion. This may be due to an
imbalance between glycolysis and glucose oxidation, resulting in an
increase in H+ production and a decrease in cardiac efficiency.
Received 6 March 1995; accepted in final form 20 June 1995.
APS Manuscript Number H211-5.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 11 July 1995.