Ammonia can exist in biological fluids as NH3 or NH4+. The proportion of total ammonia that is present as NH3 is pH-dependent, whereas the proportion present as NH4+ does not change substantially. For pH in the physiological range, NH3 concentrations are at least 100 times lower than NH4+ concentrations (pKa = 9.05). Hence total ammonia concentrations are essentially equal to NH4+ concentrations. However, even though NH3 concentrations are low compared to NH4+ levels, Noiret et al 20, using a mathematical model, have demonstrated that transmural fluxes of NH3 are quantitatively important because NH3 permeability is two orders of magnitude higher than that of NH4+. Because NH3 is a polar molecule, of similar size and dipole moment to that of water, it is able to cross renal cell membranes via some members of the aquaporin family (AQP), including AQP3, AQP8, & AQP9 21. A range of different transport systems are used to move NH4+ across renal cell membranes. Since NH4+ has essentially identical biophysical characteristics in aqueous solution as the potassium ion (K+), it is able to substitute for K+ on essentially all K+ transporters. There are many additional NH4+ transporters in the renal collecting ducts, which come into play during disturbances of acid-base balance 22.
Ammonia is known to be added to blood by the intestine and kidneys, while it is removed from blood by the liver, resting muscle, and brain. The caecum in the rabbit, which has a capacity of about 40% of the total digestive tract 2, is a major site of ammonia production, generated from the bacterial hydrolysis of amino acids and urea therein 23. The ammonia is taken from the intestine in the portal circulation to the liver. The concentration of ammonia in the portal circulation can often reach levels 10-fold higher than found elsewhere in the circulatory system. In the liver hepatocytes, the ammonia undergoes a detoxification process, that involves its conversion either to urea or glutamine. It is clear that a future study is required to appraise the extent of the conversion of portal circulation derived ammonia by the liver. Only then, will it be clear the extent to which plasma ammonia levels might be impacted by caecal ammoniagenesis.
In our study, we found that 70% of the filtered ammonia load was reabsorbed while 30% was excreted in the urine, indicating that, normal, healthy rabbits, in acid – base balance, do not add any additional intrarenal generated ammonia to the urine. This is in complete contrast to man, canine, and rodent species, where renal ammonia excretion almost entirely reflects intrarenal ammoniagenesis 6.
The reabsorbed ammonia is thought to be trapped as glutamine, due to the high glutamine synthetase activity found in the renal cortex of the rabbit kidney 24. In the renal cortex, the basal rate of glutamine synthesis has been shown to be heterogenous and differentially regulated along the proximal tubule sub – segments 25.
The data on the plasma level of ammoniagenic substrates should prove useful in enabling our current understanding of renal function in the rabbit, as well as facilitating future experimental design when investigating ammonia metabolism, and disturbances of acid – base balance in this species. The relatively high plasma levels of ammonia reported in this study require future investigations to ascertain the physiological relevance of this finding in normal, healthy rabbits.