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EDITORIAL FOCUS
Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio 44106
REGULATION OF BREATHING by changes in arterial blood gases has been the focus of interest for several decades. Although much is known about how changes in arterial blood oxygen levels influence breathing, little is known about whether tissue oxygen levels also affect breathing. Stimulation of breathing during exercise was thought to be mediated by tissue oxygenation that is sensed by chemoreceptors present in mixed venous blood where changes in tissue oxygen are reflected in metabolic rate. Experimental evidence supporting such a possibility, however, is less compelling. Birchard and Tenny (1) examined ventilatory responses to hypoxia after sodium cyanate, a compound that increases the affinity of Hb for oxygen. However, these investigators found no alterations in hypoxic ventilatory response after cyanate. Thus, whether changes in tissue oxygen affect control of breathing by hypoxia remain uncertain.
Affinity of Hb for oxygen is altered with mutations in 
- or
-chains of globin (Hb) molecule and thus can influence tissue oxygen
levels. Hb Presbyterian (HbPres) is one such mutant variation of
Hb, wherein Asn-108 of -major chain is mutated to Lys residue
(2,
3). Suzuki et al.
(6) generated mutant mice
carrying Presbyterian mutation (Asn 108 to Lys) at the -globin
locus by a targeted knock-in strategy. Homozygous mice expressed exclusively
HbPres in 100% of peripheral blood and associated with decreases in
oxygen affinity by 
3.5 mmHg (P50 values of Hb 47 mmHg in mutant vs. 43.5
mmHg in wild type). Shirasawa et al.
(5) reported that
HbPres mutant mice exhibit improved tissue oxygenation, increased
CO2 production, increased motor activity, decreased minute
ventilation, and elevated arterial PCO2. Arterial
PO2 of the mutant mice, however, was comparable to
wild-type mice (5).
HbPres mutant mice offer an excellent model to test the effects of
increased tissue oxygenation (without changes in arterial
PO2) on breathing. In this issue of the American
Journal of Physiology-Regulatory, Integrative and Comparative Physiology,
Izumizaki et al. (2a) report
that HbPres mutant mice exhibit attenuated ventilatory response to
hypoxia and hypercapnia. These observations are intriguing in that they
suggest that altered tissue oxygenation can influence breathing even in the
absence of changes in arterial PO2.
On the basis of a brief hyperoxic test (Dejour's test), Izumizaki et al. concluded that the reduced hypoxic ventilatory response is due to central mechanisms possibly involving altered processing of chemosensory information, rather than altered carotid body sensitivity to oxygen. Although this may be true, direct recording of carotid body activity is needed to substantiate this possibility. Because basal arterial PCO2 levels were elevated in mutant mice, it was suggested that the reduced hypercapnic ventilatory response was due to chronic hypercapnia. Although these possibilities require detailed investigations, alternative mechanism(s) also need to be considered. Suzuki et al. (6) noted that erythrocytes from homozygous mice had shortened life span when transfused into wild-type mice, suggesting increased hemolysis in HbPres mutant mice. Hemin, a product of heme resulting from increased hemolysis, is a potent stimulus for upregulating the enzyme heme oxygenase-1 (HO-1). Carbon monoxide (CO) is a byproduct of the chemical reaction catalyzed by HO-1, and endogenous CO influences ventilation by acting at the carotid body chemoreceptors and/or central O2 sensors (4). Therefore, monitoring carboxy Hb levels in mutant mice might provide clues as to the possible involvement of HO-1-CO system in altered breathing in HbPres mutant mice.
FOOTNOTES
Address for reprint requests and other correspondence: N. R. Prabhakar, Dept.
of Physiology & Biophysics, School of Medicine, Case Western Reserve
Univ., 10900 Euclid Ave., Cleveland, OH 44106 (E-mail:
nrp{at}po.cwru.edu).
REFERENCES
108 (G10) Asn
Lys] found in Japan.
Hemoglobin 8:
407-411, 1984.[Medline]
108 (G10) Asn Lys] in a German family.
Hemoglobin 3:
365-370, 1979.[Medline]
108 Lys) confer hemolytic anemia with altered
oxygen affinity and instability of Hb. Biochem Biophys Res
Commun 295:
869-876, 2002.[ISI][Medline]
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