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

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.

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Time-dependent phrenic nerve responses to carotid afferent activation: intact vs. decerebellate rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1993.265.4.r811 ◽

1993 ◽

Vol 265 (4) ◽

pp. R811-R819 ◽

Cited By ~ 65

Author(s):

F. Hayashi ◽

S. K. Coles ◽

K. B. Bach ◽

G. S. Mitchell ◽

D. R. McCrimmon

Keyword(s):

Phrenic Nerve ◽

Carotid Sinus ◽

Carotid Sinus Nerve ◽

Short Term ◽

Nerve Activity ◽

A Value ◽

Afferent Activation ◽

Term Potentiation ◽

Long Term Facilitation

The objectives were to determine 1) respiratory responses to carotid chemoreceptor inputs in anesthetized rats and 2) whether the cerebellar vermis plays a role in these responses. A carotid sinus nerve was stimulated (20 Hz) with five 2-min trains, each separated by approximately 3 min. During stimulation, respiratory frequency (f), peak amplitude of integrated phrenic nerve activity (integral of Phr), and their product (f x integral of Phr) immediately increased. As stimulation continued, integral of Phr progressively increased to a plateau [short-term potentiation (STP)], but f and f x integral of Phr decreased [short-term depression (STD)] to a value still above control. Upon stimulus termination, integral of Phr progressively decreased but remained above control; f and f x integral of Phr transiently decreased below baseline. After the final stimulation, integral of Phr remained above control for at least 30 min [long-term facilitation (LTF)]. Repeated 5-min episodes of isocapnic hypoxia also elicited STP, STD, and LTF. Vermalectomy lowered the CO2-apneic threshold and eliminated LTF. In conclusion, carotid chemoreceptor activation in rats elicits STP and LTF similar to that in cats; the vermis may play a role in LTF. A new response, STD, was observed.

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Short-term potentiation of carotid sinus nerve inputs to neurons in the nucleus of the solitary tract

Respiration Physiology ◽

10.1016/s0034-5687(97)00087-x ◽

1997 ◽

Vol 110 (2-3) ◽

pp. 229-236 ◽

Cited By ~ 30

Author(s):

Steven W Mifflin

Keyword(s):

Carotid Sinus ◽

Solitary Tract ◽

Carotid Sinus Nerve ◽

Short Term ◽

Term Potentiation

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Activation of Astrocytes in the Persistence of Post-hypoxic Respiratory Augmentation

Frontiers in Physiology ◽

10.3389/fphys.2021.757731 ◽

2021 ◽

Vol 12 ◽

Author(s):

Isato Fukushi ◽

Kotaro Takeda ◽

Mieczyslaw Pokorski ◽

Yosuke Kono ◽

Masashi Yoshizawa ◽

...

Keyword(s):

Acute Hypoxia ◽

Whole Body ◽

High Dose ◽

Ventilatory Responses ◽

Adult Mice ◽

Term Potentiation ◽

Before And After ◽

Whole Body Plethysmography ◽

Hypoxic Gas Mixture

Acute hypoxia increases ventilation. After cessation of hypoxia loading, ventilation decreases but remains above the pre-exposure baseline level for a time. However, the mechanism of this post-hypoxic persistent respiratory augmentation (PHRA), which is a short-term potentiation of breathing, has not been elucidated. We aimed to test the hypothesis that astrocytes are involved in PHRA. To this end, we investigated hypoxic ventilatory responses by whole-body plethysmography in unanesthetized adult mice. The animals breathed room air, hypoxic gas mixture (7% O2, 93% N2) for 2min, and again room air for 10min before and after i.p. administration of low (100mg/kg) and high (300mg/kg) doses of arundic acid (AA), an astrocyte inhibitor. AA suppressed PHRA, with the high dose decreasing ventilation below the pre-hypoxic level. Further, we investigated the role of the astrocytic TRPA1 channel, a putative ventilatory hypoxia sensor, in PHRA using astrocyte-specific Trpa1 knockout (asTrpa1−/−) and floxed Trpa1 (Trpa1f/f) mice. In both Trpa1f/f and asTrpa1−/− mice, PHRA was noticeable, indicating that the astrocyte TRPA1 channel was not directly involved in PHRA. Taken together, these results indicate that astrocytes mediate the PHRA by mechanisms other than TRPA1 channels that are engaged in hypoxia sensing.

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Integration-differentiation and gating of carotid afferent traffic that shapes the respiratory pattern

Journal of Applied Physiology ◽

10.1152/japplphysiol.00639.2002 ◽

2003 ◽

Vol 94 (3) ◽

pp. 1213-1229 ◽

Cited By ~ 25

Author(s):

Daniel L. Young ◽

Frederick L. Eldridge ◽

Chi-Sang Poon

Keyword(s):

Carotid Sinus ◽

Nucleus Tractus Solitarius ◽

Respiratory Rhythm ◽

Respiratory Pattern ◽

Carotid Sinus Nerve ◽

Short Term ◽

Time Frequency ◽

Disease States ◽

Stop And Go ◽

Term Potentiation

The phase-dependent plasticity of carotid chemoafferent signaling was studied with electrical stimulation of a carotid sinus nerve during either inspiration or expiration in anesthetized, glomectomized, vagotomized, paralyzed, and ventilated rats. Stroboscopic and interferometric analyses of the resulting phase-contrast disturbances of the respiratory rhythm revealed that carotid chemoafferent traffic was dynamically filtered centrally by a parallel bank of leaky integrators and differentiators, each being logically gated to the inspiratory or expiratory phase in a stop-and-go manner as follows: 1) carotid short-term potentiation of inspiratory drive was mediated by dual integrators that both shortened inspiration and augmented phrenic motor output cooperatively in long and short timescales; 2) carotid short-term depression of respiratory frequency was mediated by a (possibly pontine) integrator that lengthened expiration with a relatively long memory; and 3) carotid “chemoreflex” shortening of expiration was mediated by an occult fast integrator, which, together with carotid short-term depression, formed a differentiator. These effects were modulated anteriorly by integrators in the nucleus tractus solitarius that were “auto-gated” to, or recruited by, the carotid sinus nerve input. Such phase-selective and activity-dependent time-frequency filtering of carotid chemoafferent feedback in parallel neurological-neurodynamic central pathways may profoundly affect respiratory stability during hypoxia and sleep and could contribute to the dynamic optimization of the respiratory pattern and maintenance of homeostasis in health and in disease states.

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Role of Nitric Oxide in Short-Term Potentiation and Long-Term Facilitation

Advances in Experimental Medicine and Biology - Frontiers in Modeling and Control of Breathing ◽

10.1007/978-1-4615-1375-9_33 ◽

2001 ◽

pp. 215-219 ◽

Cited By ~ 8

Author(s):

David D. Kline ◽

Nanduri R. Prabhakar

Keyword(s):

Nitric Oxide ◽

Short Term ◽

Term Potentiation ◽

Long Term Facilitation

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Carotid sinus nerve transection abolishes the facilitation of breathing that occurs upon cessation of a hypercapnic gas challenge in male mice

Journal of Applied Physiology ◽

10.1152/japplphysiol.01031.2020 ◽

2021 ◽

Author(s):

Paulina M. Getsy ◽

Sripriya Sundararajan ◽

Stephen John Lewis

Keyword(s):

Carotid Sinus ◽

Ventilatory Response ◽

Minute Ventilation ◽

Nerve Transection ◽

Carotid Sinus Nerve ◽

Ventilatory Responses ◽

Bilateral Carotid ◽

Baseline Values ◽

Freely Moving

Arterial pCO2 elevations increase minute ventilation via activation of chemosensors within the carotid body (CB) and brainstem. Although the roles of CB chemoafferents in the hypercapnic (HC) ventilatory response have been investigated, there are no studies reporting the role of these chemoafferents in the ventilatory responses to a HC challenge or the responses that occur upon return to room-air, in freely-moving mice. This study found that a HC challenge (5%CO2, 21% O2, 74% N2 for 15 min) elicited an array of responses, including increases in frequency of breathing (accompanied by decreases in inspiratory and expiratory times), and increases in tidal volume, minute ventilation, peak inspiratory and expiratory flows, and inspiratory and expiratory drives in sham-operated (SHAM) adult male C57BL6 mice, and that return to room-air elicited a brief excitatory phase followed by gradual recovery of all parameters toward baseline values over a 15 min period. The array of ventilatory responses to the HC challenge in mice with bilateral carotid sinus nerve transection (CSNX) performed 7 days previously, occurred more slowly but reached similar maxima as SHAM mice. A major finding was responses upon return to room-air were dramatically lower in CSNX mice than SHAM mice, and the parameters returned to baseline values within 1-2 min in CSNX mice, whereas it took much longer in SHAM mice. These findings are the first evidence that CB chemoafferents play a key role in initiating the ventilatory responses to HC challenge in C57BL6 mice and are essential for the expression of post-HC ventilatory responses.

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