Breathing for protein function and [H+] homeostasis.

Based on a physicochemical analysis of H+ homeostasis, we hypothesize that PCO2 and strong ions, and not [H+], act independently on chemosensors 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 conformation and function. Three independent variables regulate [H+] in body fluids: P(CO2), the strong ion difference ([SID]; ([Na+] + [K+]) - ([Cl-] + [lactate-])), and total weak anion. Temperature, osmolality and strong ions affect the pK of proteins. Our data and the literature support the hypothesis that [SID] is the stimulus to central medullary chemoreceptors and ventilation. The resulting change in PCO2 counterbalances change in [SID] and maintains [H+] constant. For example, a diet low in NaCl predisposes to a high [SID] (acts to decrease [H+]); increased [SID] increases the PaCO2 threshold of the ventilatory response to CO2, decreases alveolar ventilation, and increases PCO2 to maintain [H+] 'constant'. Because ventilation is stimulated by changes in PCO2 at constant [SID], PCO2 acts independently of [SID]. As well, change in osmolality and/or angiotensin II level, associated with alterations in water and electrolyte balance, act as stimuli to ventilation and interact with chemical control. Establishing the contributions of these neural, humoral and chemical mechanisms in respiratory adaptations will provide a challenge for future investigation.