Acetoacetate effect on the isolated rat heart tolerance to anoxia

j Mol Cell Cardiol 17 (Supplement 3) (1985) 8 5 MYOCARDIAL ATP AND ADENIN NUCLEOTIDES BEFORE, DURING AND IN RE-PERFUSION PHASE AFTER CARDIOPLEGIA FOR AORTIC VALVE REPLACEMENT. E. Jansson, L. Bengtsson, A. Henze, T. Schmidt, A. Sollevi & L. Kaijser. Departments of Clinical Physiology and Thoracic surgery, Karolinska Hospital and Department of Pharmacology, Karolinska I n s t i t u t e , Stockholm, Sweden. The induction, maintenance and reperfusion phases of cardioplegia impose d i f f e r e n t problems with regard to myocardial energy preservation. In 9 patients biopsies were taken from the apex of the l e f t ventricle (1) from the beating normothermic heart, (2) in extracorporeal circulation before aortic cross clamping, (3) I-3 min l a t e r , after injection of cardioplegic solution, (4) a f t e r 30 min cardioplegia, (5) p r i o r to declamping and (6) a f t e r 45 min reperfusion. Biopsies were frozen in l i q u i d nitrogen within 2 s and analyzed by HPLC for ATP, ADP, AMP and t h e i r metabolites as well as creatine phosphate, creatine and lactate. In eight of the patients a very moderate decrease in ATP and no significant changes in ADP and AMP-concentrations took place during cardioplegia in spite of an increase in lactate indicating anaerobic metabolism. During reperfusion ATP decreased and adenosine increased s l i g h t l y . In the nineth patient stenosis of the main branch of the l e f t coronary artery impeded cardioplegia infusion. In this patient ATP decreased and adenosine increased dramatically during cardioplegia. I t is concluded that conventional cardioplegia offers good preservation of myocardial energy metabolism provided no significant coronary stenosis is at hand.

8 6 A C E T O A C E T A T E EFFECT ON THE ISOLATED RAT HEART TOLERANCE TO ANOXIA. O. G6mez-Huerga, R. Guidoux. Nestec Ltd., Research Department, CH-1800 Vevey (Switzerland). Conversion of 2-oxoglutarate (and its endogenous precursors, notably glutamate) to succinate, in the TCA cycle, is limited in anoxia by NAD availability. Providing acetoacetate (AcAc) to anoxic cells is expected to activate this pathway by permitting NADH reoxidation in mitochondria. Since metabolic flux through this pathway is coupled to energy production by substrate-level phosphorylation, which may exert a protection against anoxic damages, we evaluated the influence of AcAc on the heart tolerance to anoxia. Unpaced hearts were perfused with a Krebs bicarbonate buffer (37~ containing I0 mM pyruvate (afterload : 7.9 KPa). An aerobic anterograde perfusion (95% 02 , 5% C0~; x preload : 1.5 KPa) was made to precede and follow a 30-45 min anaerobic retrograde perfusion(95 % Np, 5% C02) at constant flow (15 ml/min). The perfusate was supplemented by 5 mM AcNc (J 5 fiLMglutamate) or pyruvate (control) during the anoxic period. Hearts of the AcAc group (n=10) recovered a better function (output : 26.1J4.0 ml/min; peak aortic pressure : I0.9+0.4 KPa, p ~ 0.05 by covariance test) than control hearts (output : 18.1+4.2 ml/min; peak aortic pressure : 9.9+0.6 KPa, n=12) after a 30 min anoxia. Heart beats and 0o consumption were not detectably different in the 2 groups. Providing glutamate together with AeAc failed to improve the recovery. After 45 min of anoxia, a significant greater proportion of hearts recovered a cardiac output in the AcAc group (9/10) than in the control group (i/5).

B 7 EFFECT OF GLUTAMIC ACID AND ITS METABOLITES ON THE HYPOXIC CONTRACTURE AND MYOCARDIAL HIGH ENERGY PHOSPHATE CONTENL V~ OoloPisarenko, EoSoSolomatina, IoM~ VoEolvanov and VoNoSmlrnovo Institute of Experimental Cardiology, USSR Cardilogy Research Center, Moscow, USSRo The benefical effect of glutamic acid on the cardiac function during hypoxia and reoxygenation has been studied~ Isolated rat hearts exhibited a rise in isovolumic d i a s t o l i c pressure during 60-min perfusion with anoxic Krebs solution, this rise did not disappear completely after 30-min reoxygenationo The presence of glutamic acid / 5 mM / in the perfusate during hypoxia and reoxygenation diminished d i a s t o l i c pressure rise by 2~ times and f a c i l i t a t e d its complete recovery during reoxygenation: Maintenance of a higher ATP level during hypoxia and reoxygenation in the presence of glutamic acid seemed not to be due to increased glycolysis as total lactate production and sum of purivate and alanine were the same~But total content of succlnate, the end product of Krebs cycle in anaerobic conditions, increased in the presence of glutamic acid more than twofold: All these effects were eliminated i f aminooxyacetic acid, a transaminase i n h i b i t o r , was added simultaneously with glutamlc acid~ Products of glutamic acid transamination, aspartic and ~ - k e t o g l u t a r i c acids /5 mM/ , induced the same functional and metabolic alterations as glutamic acido The results suggest that the benefical effect of glutamic acid may be due to increased anaerobic ATP formation in mitochondria associated with succinate production~