Respiratory Depression following Acute Hypoxia in Vagotomized and Carotid Sinus Nerve Denervated Cats

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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Bilateral carotid sinus nerve transection exacerbates morphine-induced respiratory depression

European Journal of Pharmacology ◽

10.1016/j.ejphar.2018.07.018 ◽

2018 ◽

Vol 834 ◽

pp. 17-29 ◽

Cited By ~ 6

Author(s):

Santhosh M. Baby ◽

Ryan B. Gruber ◽

Alex P. Young ◽

Peter M. MacFarlane ◽

Luc J. Teppema ◽

...

Keyword(s):

Respiratory Depression ◽

Carotid Sinus ◽

Nerve Transection ◽

Carotid Sinus Nerve ◽

Bilateral Carotid

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Carotid sinus nerve section and the increase in plasma cortisol during acute hypoxia in fetal sheep.

The Journal of Physiology ◽

10.1113/jphysiol.1994.sp020172 ◽

1994 ◽

Vol 477 (1) ◽

pp. 75-80 ◽

Cited By ~ 50

Author(s):

D A Giussani ◽

H H McGarrigle ◽

P J Moore ◽

L Bennet ◽

J A Spencer ◽

...

Keyword(s):

Plasma Cortisol ◽

Carotid Sinus ◽

Acute Hypoxia ◽

Carotid Sinus Nerve ◽

Nerve Section ◽

Fetal Sheep

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Adult carotid chemoafferent responses to hypoxia after 1, 2, and 4 wk of postnatal hyperoxia

Journal of Applied Physiology ◽

10.1152/japplphysiol.00985.2002 ◽

2003 ◽

Vol 95 (3) ◽

pp. 946-952 ◽

Cited By ~ 61

Author(s):

G. E. Bisgard ◽

E. B. Olson ◽

Z.-Y. Wang ◽

R. W. Bavis ◽

D. D. Fuller ◽

...

Keyword(s):

Phrenic Nerve ◽

Carotid Sinus ◽

Acute Hypoxia ◽

Carotid Sinus Nerve ◽

Newborn Rats ◽

Adult Rats ◽

Neural Input ◽

Hyperoxic Exposure ◽

Depressed Response

Exposing newborn rats to postnatal hyperoxia (60% O2) for 1-4 wk attenuates the ventilatory and phrenic nerve responses to acute hypoxia in adult rats. The goal of this research was to increase our understanding of the carotid chemoreceptor afferent neural input in this depressed response with different durations of postnatal hyperoxic exposure. Rats were exposed from a few days before birth to 1, 2, or 4 wk of 60% O2 and studied after 3-5 mo in normoxia. The rats were anesthetized with urethane. Whole carotid sinus nerve (CSN) responses to NaCN (40 μg/kg iv), 10 s of asphyxia and acute isocapnic hypoxia (arterial Po2 45 Torr) were determined. Mean CSN responses to stimuli after postnatal hyperoxia were reduced compared with controls. Responses in rats exposed to 1 wk of postnatal hyperoxia were less affected than those exposed to 2 and 4 wk of hyperoxia, which were equivalent to each other. These studies illustrate the importance of normoxia during the first 2 wk of life in development of carotid chemoreceptor afferent function.

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Identification and Characterization of GAL-021 as a Novel Breathing Control Modulator

Anesthesiology ◽

10.1097/aln.0000000000000844 ◽

2015 ◽

Vol 123 (5) ◽

pp. 1093-1104 ◽

Cited By ~ 12

Author(s):

Francis J. Golder ◽

Scott Dax ◽

Santhosh M. Baby ◽

Ryan Gruber ◽

Toshinori Hoshi ◽

...

Keyword(s):

Respiratory Depression ◽

Carotid Body ◽

Nonhuman Primates ◽

Carotid Sinus ◽

Carotid Sinus Nerve ◽

Morphine Analgesia ◽

Α Subunit ◽

Breathing Control ◽

Arterial Blood ◽

Ventilatory Effects

Abstract Background The authors describe the preclinical pharmacological properties of GAL-021, a novel peripheral chemoreceptor modulator. Methods The ventilatory effects of GAL-021 were characterized using tracheal pneumotachometry (n = 4 to 6), plethysmography (n = 5 to 6), arterial blood gas analyses (n = 6 to 11), and nasal capnography (n = 3 to 4) in naive animals and those subjected to morphine-induced respiratory depression. Morphine analgesia in rats was evaluated by tail-flick test (n = 6). Carotid body involvement in GAL-021 ventilatory effects was assessed by comparing responses in intact and carotid sinus nerve–transected rats. Hemodynamic effects of GAL-021 were evaluated in urethane-anesthetized rats (n = 7). The pharmacological profile of GAL-021 in vitro was investigated using radioligand binding, enzyme inhibition, and cellular electrophysiology assays. Results GAL-021 given intravenously stimulated ventilation and/or attenuated opiate-induced respiratory depression in rats, mice, and nonhuman primates, without decreasing morphine analgesia in rats. GAL-021 did not alter mean arterial pressure but produced a modest increase in heart rate. Ventilatory stimulation in rats was attenuated by carotid sinus nerve transection. GAL-021 inhibited KCa1.1 in GH3 cells, and the evoked ventilatory stimulation was attenuated in Slo1−/− mice lacking the pore-forming α-subunit of the KCa1.1 channel. Conclusions GAL-021 behaved as a breathing control modulator in rodents and nonhuman primates and diminished opioid-induced respiratory depression without compromising opioid analgesia. It acted predominantly at the carotid body, in part by inhibiting KCa1.1 channels. Its preclinical profile qualified the compound to enter clinical trials to assess effects on breathing control disorders such as drug (opioid)-induced respiratory depression and sleep apnea.

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Blood Pressure Regulation by the Carotid Sinus Nerve: Clinical Implications for Carotid Body Neuromodulation

Frontiers in Neuroscience ◽

10.3389/fnins.2021.725751 ◽

2022 ◽

Vol 15 ◽

Author(s):

Silvia V. Conde ◽

Joana F. Sacramento ◽

Bernardete F. Melo ◽

Rui Fonseca-Pinto ◽

Mario I. Romero-Ortega ◽

...

Keyword(s):

Blood Pressure ◽

Nervous System ◽

Sympathetic Nervous System ◽

Metabolic Diseases ◽

Carotid Sinus ◽

Acute Hypoxia ◽

Therapeutic Modality ◽

Carotid Sinus Nerve ◽

Peripheral Chemoreceptor ◽

Sympathetic Nervous

Chronic carotid sinus nerve (CSN) electrical modulation through kilohertz frequency alternating current improves metabolic control in rat models of type 2 diabetes, underpinning the potential of bioelectronic modulation of the CSN as a therapeutic modality for metabolic diseases in humans. The CSN carries sensory information from the carotid bodies, peripheral chemoreceptor organs that respond to changes in blood biochemical modifications such as hypoxia, hypercapnia, acidosis, and hyperinsulinemia. In addition, the CSN also delivers information from carotid sinus baroreceptors—mechanoreceptor sensory neurons directly involved in the control of blood pressure—to the central nervous system. The interaction between these powerful reflex systems—chemoreflex and baroreflex—whose sensory receptors are in anatomical proximity, may be regarded as a drawback to the development of selective bioelectronic tools to modulate the CSN. Herein we aimed to disclose CSN influence on cardiovascular regulation, particularly under hypoxic conditions, and we tested the hypothesis that neuromodulation of the CSN, either by electrical stimuli or surgical means, does not significantly impact blood pressure. Experiments were performed in Wistar rats aged 10–12 weeks. No significant effects of acute hypoxia were observed in systolic or diastolic blood pressure or heart rate although there was a significant activation of the cardiac sympathetic nervous system. We conclude that chemoreceptor activation by hypoxia leads to an expected increase in sympathetic activity accompanied by compensatory regional mechanisms that assure blood flow to regional beds and maintenance of hemodynamic homeostasis. Upon surgical denervation or electrical block of the CSN, the increase in cardiac sympathetic nervous system activity in response to hypoxia was lost, and there were no significant changes in blood pressure in comparison to control animals. We conclude that the responses to hypoxia and vasomotor control short-term regulation of blood pressure are dissociated in terms of hypoxic response but integrated to generate an effector response to a given change in arterial pressure.

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