title: Demand-induced ischemia in volume expanded isolated rat heart; the effect of dichloroacetate and trimetazidine.
abstract: In failing hearts, coronary flow is normal, but the coronary flow reserve (CFR) is reduced, so demand-induced ischemia (DII) may occur in response to greater demand for O(2). The objectives of this study were: (i) to verify that dobutamine stimulation produces DII in isolated rat hearts having, like failing hearts, increased left ventricular end-diastolic pressure (LVEDP) and hence reduced CFR and (ii) to study the effects of stimulation of glucose oxidation and of inhibition of fatty acid oxidation in this new model of DII. Isolated rat hearts perfused with 11 mM glucose and 0.6 mM palmitate (or no palmitate) were studied. Stepwise increments in the volume of a balloon placed in LV resulted in reciprocal impairment of CFR, supporting the role of the extravascular compressive forces in determining CFR. CFR was 1.82+/-0.1 and 1.32+/-0.1 (p<0.05) in the hearts with LVEDP set to 5 mmHg (controls) and 40 mmHg (expanded), respectively. In controls, dobutamine increased coronary flow, myocardial oxygen consumption (MVO(2)), LVDP, mechanical efficiency, and the rates of palmitate and glucose oxidation, however, the effluent lactate concentration remained unchanged. In the expanded hearts vs. controls, dobutamine-induced increases in coronary flow and MVO(2) were reduced by approximately 50%, the increases in LVDP, efficiency, and rates of glucose and fatty acid oxidation were completely prevented, and lactate production greatly increased with dobutamine, indicating DII. Pyruvate dehydrogenase activator, dichloroacetate (DCA 1 mM) and a putative inhibitor of fatty acid beta-oxidation, trimetazidine (5 microM), both increased the rate of glucose oxidation and attenuated myocardial lactate production during DII, however they did not improve myocardial function during DII. Likewise, palmitate-free perfusion had no beneficial effect during DII although it attenuated lactate production. In the hearts subjected to palmitate-free perfusion plus DCA, lactate overproduction during DII was completely abolished, however, the deterioration of LVDP and mechanical efficiency was only partially prevented. Thus, greater demand for O(2) induces DII in the expanded hearts with reduced CFR. Lactate overproduction secondary to an imbalance between glycolysis and glucose oxidation is not a primary factor adversely affecting cardiac mechanical function during DII. Interventions shifting this balance toward glucose oxidation are not beneficial in the setting of DII in our model although they are known to effectively mitigate contractile dysfunction in the post-ischemic myocardium.
authors.affiliation: Department of Clinical Physiology, Medical Centre for Postgraduate Education, Warsaw, Poland.
authors.forename: A
authors.initials: A
authors.lastname: Skierczynska
authors.forename: A
authors.initials: A
authors.lastname: Beresewicz
mesh_terms: D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D004195:Disease Models, Animal; D004280:Dobutamine / Q000008:administration & dosage*; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000008:administration & dosage / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D008297:Male; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000503:physiopathology*; D010084:Oxidation-Reduction / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D019308:Palmitic Acid / Q000008:administration & dosage / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014292:Trimetazidine / Q000494:pharmacology*
chemical_list: D005227:Fatty Acids; D019308:Palmitic Acid; D004280:Dobutamine; D003999:Dichloroacetic Acid; D005947:Glucose; D014292:Trimetazidine