Pathways of succinate formation and their contribution to improvement of cardiac function in the hypoxic rat heart.
Hypoxia led to a dramatic acceleration of amino acid breakdown together with succinate synthesis in the rat heart. Our data do not confirm the simultaneous conversion of aspartate and glutamate to succinate, which has been repeatedly assumed in the literature (7, 8, 21, 28-30), but rather suggest that different pathways are involved during developing hypoxia and that glutamate is the sole source for anaerobic succinate production from endogenous sources in the glucose-perfused heart. Perfusion of hypoxic rat hearts with 2-oxoglutarate, malate, and fumarate (5 mM each) increased succinate formation three- to fourfold. The beneficial effects of these substances on left ventricular systolic pressure, end diastolic pressure, and time of recovery may be due to the elevated content of ATP in these hearts compared to hypoxic controls with glucose as the sole substrate. However, the maintenance of a high rate of anaerobic glycolysis in hearts perfused with 2-oxoglutarate, malate, and fumarate and not the small stimulation of succinate synthesis is considered to be the most important mechanism of cardiac protection. A proposed pathway assumes that malate, after dehydration to fumarate, may serve as an alternative electron acceptor for cytosolic NADH during conditions of oxygen deficiency, thereby cancelling glycolytic inhibition.
Wiesner
R J
RJ
Instutit für Zoologie IV, Universität Düsseldorf, Federal Republic of Germany.
Rösen
P
P
Grieshaber
M K
MK
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002952:Citric Acid Cycle / Q000187:drug effects; D003327:Coronary Disease / Q000503:physiopathology*; D003998:Dicarboxylic Acids / Q000494:pharmacology; D004734:Energy Metabolism / Q000187:drug effects; D006321:Heart / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values; D013386:Succinates / Q000096:biosynthesis / Q000502:physiology*
D000596:Amino Acids; D003998:Dicarboxylic Acids; D013386:Succinates