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J Appl Physiol (1985). 2014 May 15;116(10):1290-9. doi: 10.1152/japplphysiol.01050.2013. Epub 2014 Mar 7.

Essential role of hemoglobin beta-93-cysteine in posthypoxia facilitation of breathing in conscious mice.

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Pediatric Respiratory Medicine, University of Virginia School of Medicine, Charlottesville, Virginia;
Pediatric Respiratory Medicine, University of Virginia School of Medicine, Charlottesville, Virginia;
Department of Anesthesia, University of Iowa Hospitals and Clinics, Iowa City, Iowa; and.
Department of Pediatrics, Rainbow Babies and Children's Hospital, Cleveland, Ohio.


When erythrocyte hemoglobin (Hb) is fully saturated with O2, nitric oxide (NO) covalently binds to the cysteine 93 residue of the Hb β-chain (B93-CYS), forming S-nitrosohemoglobin. Binding of NO is allosterically coupled to the O2 saturation of Hb. As saturation falls, the NO group on B93-CYS is transferred to thiols in the erythrocyte, and in the plasma, forming circulating S-nitrosothiols. Here, we studied whether the changes in ventilation during and following exposure to a hypoxic challenge were dependent on erythrocytic B93-CYS. Studies were performed in conscious mice in which native murine Hb was replaced with human Hb (hB93-CYS mice) and in mice in which murine Hb was replaced with human Hb containing an alanine rather than cysteine at position 93 on the Bchain (hB93-ALA). Both strains expressed human γ-chain Hb, likely allowing a residual element of S-nitrosothiol-dependent signaling. While resting parameters and initial hypoxic (10% O2, 90% N2) ventilatory responses were similar in hB93-CYS mice and hB93-ALA mice, the excitatory ventilatory responses (short-term potentiation) that occurred once the mice were returned to room air were markedly diminished in hB93-ALA mice. Further, short-term potentiation responses were virtually absent in mice with bilateral transection of the carotid sinus nerves. These data demonstrate that hB93-CYS plays an essential role in mediating carotid sinus nerve-dependent short-term potentiation, an important mechanism for recovery from acute hypoxia.


S-nitrosothiol; S-nitrosylation; hemoglobin; hypoxia; posthypoxia; ventilation

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