H is maintained constant in the internal environment at a given body temperature independent of external environment according to Bernard's principle of "milieu interieur". But CO2 relates to ventilation and H+ to kidney. Hence, the title of the chapter. In order to do this, sensors for H+ in the internal environment are needed. The sensor-receptor is CO2/H+ sensing. The sensor-receptor is coupled to integrate and to maintain the body's chemical environment at equilibrium. This chapter dwells on this theme of constancy of H+ of the blood and of the other internal environments. [H+] is regulated jointly by respiratory and renal systems. The respiratory response to [H+] originates from the activities of two groups of chemoreceptors in two separate body fluid compartments: (A) carotid and aortic bodies which sense arterial P-O2, and H+; and (B) the medullary H+ receptors on the ventrolateral medulla of the central nervous system (CNS). The arterial chemoreceptors function to maintain arterial P-O2 and H+ constant, and medullary H+ receptors to maintain H+ of the brain fluid constant. Any acute change of H. in these compartments is taken care of almost instantly by pulmonary ventilation, and slowly by the kidney. This general theme is considered in Section 1. The general principles involving cellular CO2 reactions mediated by carbonic anhydrase (CA), transport of CO2 and H+ are described in Section 2. Since the rest of the chapter is dependent on these key mechanisms, they are given in detail, including the role of Jacobs-Stewart Cycle and its interaction with carbonic anhydrase. Also, this section deals briefly with the mechanisms of membrane depolarization of the chemoreceptor cells because this is one mechanism on which the responses depend. The metabolic impact of endogenous CO2 appears in the section with a historical twist, in the context of acclimatization to high altitude (Section 3). Because low P-O2 at high altitude stimulates the peripheral chemoreceptors (PC) increasing ventilation, the endogenous CO2 is blown off, making the internal milieu alkaline. With acclimatization however ventilation increases. This alkalinity is compensated in the course of time by the kidney and the acidity tends to be restored, but the acidification is not (,real enough to increase ventilation further. The question is what drives ventilation during acclimatization when the central pH is alkaline? The peripheral chemoreceptor came to the rescue. Its sensitivity to P-O2 is increased which continues to drive ventilation further during acclimatization at high altitude even when pH is alkaline. This link of CO2 through the O-2 chemoreceptor is described in Section 4 which led to hypoxia-inducible factor (HIF-1). HIF-1 is stabilized during hypoxia, including the carotid body (CB) and brain cells, the seat of CO2 chemoreception. The cells are always hypoxic even at sea level. But how CO can affect the HIF-1 in the brain is considered in this section. CO2 sensing in the central chemoreceptors (CC) is given in Section 5 CO2/H+ is sensed by the various structures in the central nervous system but its respiratory and cardiovascular responses are restricted only to some areas. How the membranes are depolarized by CO or how it works through Na+/Ca2+ exchange are discussed in this section. It is obvious, however, that CO2 is not maintained constant, decreasing with altitude as alveolar PO2 decreases and ventilation increases. Rather, it is the [H+] that the organism strives to maintain at the expense of CO2. But then again, [H+] where? Perhaps it is in the intracellular environment. Gap junctions in the carotid body and in the brain are ubiquitous. What functions they perform have been considered in Section 6. CO2 changes take place in lung alveoli where inspired air mixes with the CO,) from the returning venous blood. It is the interface between the inspired and expired air in the lungs where CO2 change is most dramatic. As a result, various investigators have looked for CO2 receptors in the lung, but none have been found in the mammals. Instead, CO2/H+ receptors were found in birds and amphibians. However, they are inhibited by increasing CO2/H+, instead of stimulated. But the afferent impulses transmitted to the brain produced stimulation in the efferents. This reversal of afferent-efferent inputs is a curious situation in nature, and this is considered in Section 7. The NO and CO effects on CO2 sensing are interesting and have been briefly mentioned in Section 8. A model for CO2/H+ sensing by cells, neurons and bare nerve endings are also considered. These NO effects, models for CO2/H+ and O-2-sensitive cells in the CNS have been considered in the perspectives. Finally, in conclusion, the general theme of constancy of internal environment for CO2/H+ is reiterated, and for that CO2/H+ sensors-receptors systems are essential. Since CO2/H+ sensing as such has not been reviewed before, the recent findings in addition to defining basic CO2/H+ reactions in the cells have been briefly summarized. (C) 2003 Published by Elsevier Science Ltd.
