Infusion of ketone bodies was aimed at introducing beta-hydroxybutyric acid into the liquid media of dogs, which in turn led to a state of temporary ketonemia and ammonia genesis. Early sources confirmed that ammonium chloride has a ketogenic effect on the body, which should result in a severe increase in ketone concentration.
In the current study, however, a paradoxical relationship was observed in which infusion of ketone bodies led, in contrast, to a decrease in urinary ammonia excretion, and this dynamic was even measured quantitatively. Lemieux et al. reported that the decrease in ammonia genesis activity one hour after the infusion was up to 60%. As a consequence, the assumption can be made that ketone bodies depress renal ammonia genesis.
Since the assumptions about the low availability of amino acids to the renal cells were not confirmed, the probable cause of the decreased ammonia excretion in the urine was the high glutamine content in the blood of dogs. Glutamine is known to be able to inhibit ketogenesis in the liver, and thus an imbalance of ketone bodies in the renal tubules and, consequently, the formation of free ammonium ions as a product of ammonia genesis was not observed due to the overriding effect of the amino acid glutamine.
Like ketone bodies, glutamine is able to become a source of energy for the animal body in the absence of glucose, so the crucial role in restraining ammonia excretion could be explained precisely by the acceptable content of these molecules in dogs. This effect could have been mediated by the loss of electrons from the NADH molecule, resulting in this transformation into an oxidized form of NAD+. In turn, the NADH/NAD+ balance is positively related to ketogenesis — see equations above — which means that suppression of this transformation could have caused the opposite effect.
This was probably the case because the reactions of alpha-ketoglutarate conversion to glutamate under the action of glutamate dehydrogenase also result in NADH consumption and ammonia consumption. In short, one potential reason for such seemingly paradoxical effects changes in glutamate transformations in the body that suppress ketogenesis in the renal tubules.
The explanation may be alternative but also related to the functions of glutamine in the body. The amino acid glutamine is known to be able to convert to ketoglutarate by the equation:
In this case, the emitting ammonia should, at first glance, be routed through the blood to the urine, causing an excess of ammonia in the urine. However, it is likely that the introduction of ketone bodies may also inhibit the reduction reactions to alpha-ketoglutarate, resulting in no ammonia being produced and, thus, no ammonia genesis in the renal tubules. In short, there is no precise reason ketone body infusion causes the paradoxical effects of inhibiting ammonia genesis, but it is clear that it is most likely related to the metabolic activity of glutamate.