Based on a physicochemical analysis of H+ homeostasis, we hypothesize
that P(CO2) and strong ions, and not [H+], act independently on chemos
ensors in the central nervous system to regulate ventilation. [H+] in
body fluids and the pK of histidine imidazole groups of proteins must
be regulated in relation to each other to preserve protein conformatio
n and function. Three independent variables regulate [H+] in body flui
ds: P(CO2), the strong ion difference ([SID]; ([Na+] + [K+]) - ([Cl-]
+ [lactate-])), and total weak anion.Temperature, osmolality and stron
g ions affect the pK of proteins. Our data and the literature support
the hypothesis that [ SID] is the stimulus to central medullary chemor
eceptors and ventilation. The resulting change in P(CO2) counterbalanc
es change in [SID] and maintains [H+] constant. For example, a diet lo
w in NaCl predisposes to a high [SID] (acts to decrease [H+]) increase
d [SID] increases the Pa(CO2) threshold of the ventilatory response to
CO2, decreases alveolar ventilation, and increases P(CO2) to maintain
[H+] 'constant'. Because ventilation is stimulated by changes in P(CO
2) at constant [SID], P(CO2) acts independently of [SID]. As well, cha
nge is osmolality and/or angiotensin II level, associated with alterat
ions in water and electrolyte balance, act as stimuli to ventilation a
nd interact with chemical control. Establishing the contributions of t
hese neural, humoral and chemical mechanisms in respiratory adaptation
s will provide a challenge for future investigation.