H2S mediates carotid body response to hypoxia but not anoxia

Abstract

The role of cystathionine-γ-lyase (CSE) derived HS in the hypoxic and anoxic responses of the carotid body (CB) were examined. Experiments were performed on Sprague-Dawley rats, wild type and CSE knockout mice on C57BL/6 J background. Hypoxia (pO = 37 ± 3 mmHg) increased the CB sensory nerve activity and elevated HS levels in rats. In contrast, anoxia (pO = 5 ± 4 mmHg) produced only a modest CB sensory excitation with no change in HS levels. DL-propargylglycine (DL-PAG), a blocker of CSE, inhibited hypoxia but not anoxia-evoked CB sensory excitation and [Ca] elevation of glomus cells. The inhibitory effects of DL-PAG on hypoxia were seen: a) when it is dissolved in saline but not in dimethyl sulfoxide (DMSO), and b) in glomus cells cultured for18 h but not in cells either soon after isolation or after prolonged culturing (72 h) requiring 1-3 h of incubation. On the other hand, anoxia-induced [Ca] responses of glomus cell were blocked by high concentration of DL-PAG (300μM) either alone or in combination with aminooxyacetic acid (AOAA; 300μM) with a decreased cell viability. Anoxia produced a weak CB sensory excitation and robust [Ca] elevation in glomus cells of both wild-type and CSE null mice. As compared to wild-type, CSE null mice exhibited impaired CB chemo reflex as evidenced by attenuated efferent phrenic nerve responses to brief hyperoxia (Dejours test), and hypoxia. Inhalation of 100% N (anoxia) depressed breathing in both CSE null and wild-type mice. These observations demonstrate that a) hypoxia and anoxia are not analogous stimuli for studying CB physiology and b) CSE-derived HS contributes to CB response to hypoxia but not to that of anoxia.

Recent advances in understanding the physiology of hypoxic sensing by the carotid body

“…CB sensory and type I cell responses to anoxia were unaffected by CSE inhibitors and in CSE knockout mice. Moreover, anoxia (100% N 2 ) depressed breathing whereas hypoxia (12% O 2 ) stimulated breathing 5 . CSE knockout mice showed an absence of breathing stimulation by hypoxia, whereas the depressed breathing by anoxia was unaffected in these mice 5 .…”

“…Type I cell responses to acute hypoxia are measured by monitoring exocytosis and changes in [Ca 2+ ] i and K + channel conductance 1 . Although type I cells respond to hypoxia with elevated [Ca 2+ ] i or K + channel inhibition (or both), they are not always reflected in the sensory nerve activity 4, 5 , which is essential for evoking the physiologically important CB chemo reflex. Therefore, it is necessary to corroborate the cellular responses to hypoxia with the sensory nerve discharge for assessing the physiological relevance of CB hypoxic sensing.…”

“…Peng et al . 5 re-examined the role for CSE-derived H 2 S in the CB sensory nerve and type I cell [Ca 2+ ] i responses to hypoxia (pO 2 of about 37 mmHg) and anoxia (pO 2 of about 5 mmHg). The authors found that hypoxia increased H 2 S levels in the CB, stimulated sensory nerve activity, and elevated [Ca 2+ ] i in type I cells and all of these responses were blocked by a CSE inhibitor and in CSE knockout mice.…”

The Carotid Body a Common Denominator for Cardiovascular and Metabolic Dysfunction?

“…Neuropeptides like Substance P, enkephalins, endothelin, and angiotensin II are also present in glomus cells, and so are gaseous neurotransmitters. The glomus cells contain the enzymes required for the synthesis of H 2 S and CO (Peng et al, 2010(Peng et al, , 2017(Peng et al, , 2019. The generation of H 2 S in glomus cells appears to be a very important mediator in the chemosensory function of the carotid body as highlighted by studies in which the prevention of the generation of H 2 S resulted in the impairment of the respiratory responses induced by hypoxia (Peng et al, 2010(Peng et al, , 2017.…”

“…The generation of H 2 S in glomus cells appears to be a very important mediator in the chemosensory function of the carotid body as highlighted by studies in which the prevention of the generation of H 2 S resulted in the impairment of the respiratory responses induced by hypoxia (Peng et al, 2010(Peng et al, , 2017. It has been hypothesized that hypoxia induces a reduction of CO production within the glomus cells and this enables increased production of H 2 S. This appears to contribute to the activation of glomus cells following hypoxic but not anoxic conditions (Peng et al, 2019).…”