Hypercapnia causes cellular oxidation and nitrosation in addition to acidosis: implications for CO2 chemoreceptor function and dysfunction

Abstract

Cellular mechanisms of CO2 chemoreception are discussed and debated in terms of the stimuli produced during hypercapnic acidosis and their molecular targets: protons generated by the hydration of CO2 and dissociation of carbonic acid, which target membrane-bound proteins and lipids in brain stem neurons. The CO2 hydration reaction, however, is not the only reaction that CO2 undergoes that generates molecules capable of modifying proteins and lipids. Molecular CO2 also reacts with peroxynitrite (ONOO-), a reactive nitrogen species (RNS), which is produced from nitric oxide (*NO) and superoxide (*O2-). The CO2/ONOO- reaction, in turn, produces additional nitrosative and oxidative reactive intermediates. Furthermore, protons facilitate additional redox reactions that generate other reactive oxygen species (ROS). ROS/RNS generated by these redox reactions may act as additional stimuli of CO2 chemoreceptors since neurons in chemosensitive areas produce both *NO and *O2- and, therefore, ONOO-. Perturbing *NO, *O2-, and ONOO- activities in chemosensitive areas modulates cardiorespiration. Moreover, neurons in at least one chemosensitive area, the solitary complex, are stimulated by cellular oxidation. Together, these data raise the following two questions: 1) do pH and ROS/RNS work in tandem to stimulate CO2 chemoreceptors during hypercapnic acidosis; and 2) does nitrosative stress and oxidative stress contribute to CO2 chemoreceptor dysfunction? To begin considering these two issues and their implications for central chemoreception, this minireview has the following three goals: 1) summarize the nitrosative and oxidative reactions that occur during hypercapnic acidosis and isocapnic acidosis; 2) review the evidence that redox signaling occurs in chemosensitive areas; and 3) review the evidence that neurons in the solitary complex are stimulated by cellular oxidation.

Fig. 1.

Schematic of the relationships between hypercapnic acidosis [respiratory acidosis; reactions (Rxns) 7a and 7b] and isocapnic acidosis (metabolic acidosis; Rxn 12) and production of nitrosative and oxidative intermediates via peroxynitrite (ONOO⁻; Rxns 5 and 6) and production of oxidative intermediates via the Fenton reaction (Rxn 10). Molecular oxygen produces both superoxide anion (^•O₂⁻) and nitric oxide (^•NO) as described in the text (Rxns 1 and 2). These 2 ubiquitous radicals react to generate ONOO⁻ (Rxn 3), which in a CO₂/HCO₃⁻-buffered system (Rxn 8) immediately reacts with CO₂ to form nitrosoperoxocarboxylate (ONO₂CO₂⁻; Rxn 5) that is followed by several additional reactions summarized in the text; see also Vesela and Wilhelm (91). The most important reaction, in the context of the present discussion, is formation of carbonate radicals (CO₃^−•) and nitrogen dioxide radicals (^•NO₂) (Rxn 6). In the process, CO₂ is regenerated and recycled for production of more ONO₂CO₂⁻ (Rxn 9). In addition, ^•O₂⁻ (Rxn 1) is converted to hydrogen peroxide (H₂O₂) in a reaction catalyzed by superoxide dismutase (SOD; Rxn 4) and reacts with iron liberated from transferrin. Decreased pH increases dissociation of iron from transferrin (Rxns 7b and 12) and accelerates the Fenton reaction rightward, producing hydroxyl radicals (^•OH; Rxn 10). Metabolic acidosis (i.e., ↑H⁺, ↓HCO₃⁻, and no change Pco₂) is a more effective stimulus than respiratory acidosis (i.e., ↑H⁺, ↑HCO₃⁻, and ↑Pco₂) for liberating free iron since HCO₃⁻ promotes binding of iron to transferrin (Rxn 11). CA, carbonic anhydrase; NO₃⁻, nitrate anion; OH⁻, hydroxyl anion; solid black arrowhead, acceleration of reaction; open circle, inhibition of reaction; open arrowhead with thick line, cellular consequence of reaction, include acidosis, nitro-oxidation, and lipid peroxidation.