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The Breathing Control Puzzle during Chronic Acid–Base Imbalance

We thank Dr. Marinov and colleagues for their comments on our article (1). Concerning the animals' state of metabolic acidosis, it is important to know that they received alimentary alkali reduction for 5 days and an additional application of NH₄Cl via drinking water on Days 4 and 5. As the net renal acid excretion had reached its plateau at Day 4, animals were under steady-state conditions at the time of NHE3 determination.

The extrarenal metabolism of ammonium, especially the role of the liver in acid–base regulation, was considered as early as 1921 by J. B. S. Haldane, who first discovered metabolic acidosis upon oral intake of ammonium chloride (2). He assumed that NH₄Cl in the liver was metabolized into urea so that the remaining hydrochloric acid was the final cause of metabolic acidosis. However, Winterstein found no experimental evidence for this assumption, showing that NH₄Cl acidosis also developed when the whole blood circulation through the liver was surgically interrupted (3). To incorporate the phenomena of NH₄Cl acidosis and ventilation into his "reaction theory," Winterstein proposed that the small amount of ammonia present at physiological pH diffuses readily through lipid membranes and leaves hydrochloric acid in the extracellular space (4). Indeed, an initial extracellular acidification along with transient intracellular alkalinity could be observed in organotypic cultures of chemosensitive medullary neurons subjected to bath application of NH₄Cl (5).

Although urea genesis in the liver, in principle, could further add to metabolic acidosis, it is noteworthy that the urea cycle flux itself is inhibited by low pH. In line with this, we did not observe any significant change in renal urea excretion rate, urea serum level, or renal ammonium excretion upon treatment with NH₄Cl (unpublished observations). Thus, the contribution of interactive hepatic/renal nitrogen metabolism—if any—is expected to be very small, at least in the herbivore rabbit.

Heidrun Kiwull-Schöne

Ruhr University
Bochum, Germany

Martin Wiemann

University of Duisburg-Essen
Essen, Germany

FOOTNOTES

Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

REFERENCES

1. Kiwull-Schöne H, Kiwull P, Frede S, Wiemann M. Role of brainstem sodium/proton exchanger 3 for breathing control during chronic acid–base imbalance. Am J Respir Crit Care Med 2007;176:513–519.[Abstract/Free Full Text]
2. Haldane JBS. Experiments on the regulation of the blood's alkalinity: II. J Physiol 1921;55:265–275.[Free Full Text]
3. Winterstein H, Gökhan N. Das Wesen der Ammoniumchlorid-Acidose [The nature of ammonium chloride acidosis]. Pflugers Arch 1952;256:85–86.[CrossRef][Medline]
4. Kiwull-Schöne H. The "reaction theory" of Hans Winterstein (1879–1963) in the light of today's research on the ventrolateral medulla. In: Trouth CO, Millis RM, Kiwull-Schöne HF, Schläfke ME, editors. Ventral brainstem mechanisms and control of respiration and blood pressure. New York: Marcel Dekker; 1995. pp. 1–39.
5. Wiemann M, Baker RE, Bonnet U, Bingmann D. CO₂-sensitive medullary neurons: activation by intracellular ascidification. Neuroreport 1998;9:167–170.[Medline]

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