The heart must function properly to perform its essential role in supplying the body with the oxygen and nutrients required for survival. Over the course of a lifetime the heart will eventually be exposed to conditions of oxygen depletion or obstructed flow. At such times it is essential that the heart maintain its function and adapt to these conditions by altering its metabolism in response to the decrease in oxygen. Glucose, fatty acids, lactate and most other substrates require oxygen for full energy yield, making them unsuitable during an anoxic or ischemic period.
Amino acids have a wide array of uses in the body, including as metabolic substrates. In particular, glutamine and glutamate can be easily converted to α-ketoglutarate and shuttled into the TCA cycle as metabolic substrates. For this reason we hypothesized that it may be possible to prolong cardiac function during and improve recovery after oxygen depletion by supplying the heart with excess glutamine and glutamate.
Using action potential duration (APD) as a readout for the electrical function of the heart, we exposed rabbit hearts to anoxic and ischemic challenges and monitored their behavior. We show that elevated levels of glutamate and glutamine increased APD90 in anoxic hearts by 11% over controls. In ischemic hearts, however, the effects were even greater, as the enriched hearts had a 29% increase in APD90 and a 38% increase in APD50 compared to controls. We also demonstrate that blockage of amino acid transamination eliminates this effect and show that metabolism of these amino acids through the TCA cycle is the primary mechanism. These results are significant and conserved across both anoxia and ischemia, indicating that this could be a reliable and effective intervention for extending APD and possibly improving cardiac function.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-11172015-132931 |
| Date | 19 November 2015 |
| Creators | Drake, Kenneth James |
| Contributors | Tony Weil, Owen McGuinness, John McLean, David Wasserman, Jamey Young |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-11172015-132931/ |
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