Integration of hindbrain and carotid body mechanisms that control the autonomic response to cardiorespiratory and glucoprivic insults

Kakall, Zohra M.; Cohen, E. Myfanwy; Farnham, Melissa M.J.; Kim, Seung Jae; Nedoboy, Polina E.; Pilowsky, Paul M.

doi:10.1016/j.resp.2018.08.008

Cited by 4 publications

(3 citation statements)

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“…It is worth noting that 2-DG is a glucose analog that competes for glucose uptake and is therefore a potent inhibitor of glycolysis. The systemic administration of 2-DG produces hyperglycemia and initiates the sympathoadrenal counterregulatory response causing both epinephrine and glucagon to be released peripherally (21–24). Although a similar subset of medullary neurons is activated after either 2-DG or insulin injections, the physiological mechanisms underlying HAAF must be determined with models of insulin-induced hypoglycemia, rather than glucoprivation, to maintain biological relevance.…”

Section: Discussionmentioning

confidence: 99%

Repetitive hypoglycemia reduces activation of glucose-responsive neurons in C1 and C3 medullary brain regions to subsequent hypoglycemia

Kakall

Kavurma

Cohen

et al. 2019

American Journal of Physiology-Endocrinology and Metabolism

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The impaired ability of the autonomic nervous system to respond to hypoglycemia is termed “hypoglycemia-associated autonomic failure” (HAAF). This life-threatening phenomenon results from at least two recent episodes of hypoglycemia, but the pathology underpinning HAAF remains largely unknown. Although naloxone appears to improve hypoglycemia counterregulation under controlled conditions, hypoglycemia prevention remains the current mainstay therapy for HAAF. Epinephrine-synthesizing neurons in the rostroventrolateral (C1) and dorsomedial (C3) medulla project to the subset of sympathetic preganglionic neurons that regulate peripheral epinephrine release. Here we determined whether or not C1 and C3 neuronal activation is impaired in HAAF and whether or not 1 wk of hypoglycemia prevention or treatment with naloxone could restore C1 and C3 neuronal activation and improve HAAF. Twenty male Sprague-Dawley rats (250–300 g) were used. Plasma epinephrine levels were significantly increased after a single episode of hypoglycemia ( n = 4; 5,438 ± 783 pg/ml vs. control 193 ± 27 pg/ml, P < 0.05). Repeated hypoglycemia significantly reduced the plasma epinephrine response to subsequent hypoglycemia ( n = 4; 2,179 ± 220 pg/ml vs. 5,438 ± 783 pg/ml, P < 0.05). Activation of medullary C1 ( n = 4; 50 ± 5% vs. control 3 ± 1%, P < 0.05) and C3 ( n = 4; 45 ± 5% vs. control 4 ± 1%, P < 0.05) neurons was significantly increased after a single episode of hypoglycemia. Activation of C1 ( n = 4; 12 ± 3%, P < 0.05) and C3 ( n = 4; 19 ± 5%, P < 0.05) neurons was significantly reduced in the HAAF groups. Hypoglycemia prevention or treatment with naloxone did not restore the plasma epinephrine response or C1 and C3 neuronal activation. Thus repeated hypoglycemia reduced the activation of C1 and C3 neurons mediating adrenal medullary responses to subsequent bouts of hypoglycemia.

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Section: Discussionmentioning

confidence: 99%

Repetitive hypoglycemia reduces activation of glucose-responsive neurons in C1 and C3 medullary brain regions to subsequent hypoglycemia

Kakall

Kavurma

Cohen

et al. 2019

American Journal of Physiology-Endocrinology and Metabolism

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“…The hypoglycemia-induced AVP release counteracts low plasma concentrations of glucose by gluconeogenic and glycogenolytic effects of AVP in the liver and on the AVP-induced activation of the hypothalamic-pituitary-adrenal cortex axis resulting in glucocorticoid release ( Nakamura et al, 2017 ; Szczepanska-Sadowska et al, 2017 ). Both experimental studies in animals and clinical observations in humans suggest that carotid bodies may be involved in mediating the counter-regulatory response to decreased blood glucose ( Koyama et al, 2000 ; Wehrwein et al, 2015 ; Kakall et al, 2019 ). Both in men and rats, hypoglycemia also induces pronounced hyperventilation, which depends on the release of humoral factors, such as adrenaline acting at the carotid bodies ( Bin-Jaliah et al, 2004 ; Ward et al, 2007 ; Thompson et al, 2016 ).…”

Section: Physiology Of Vasopressinmentioning

confidence: 99%

Vasopressin and Breathing: Review of Evidence for Respiratory Effects of the Antidiuretic Hormone

et al. 2021

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Vasopressin (AVP) is a key neurohormone involved in the regulation of body functions. Due to its urine-concentrating effect in the kidneys, it is often referred to as antidiuretic hormone. Besides its antidiuretic renal effects, AVP is a potent neurohormone involved in the regulation of arterial blood pressure, sympathetic activity, baroreflex sensitivity, glucose homeostasis, release of glucocorticoids and catecholamines, stress response, anxiety, memory, and behavior. Vasopressin is synthesized in the paraventricular (PVN) and supraoptic nuclei (SON) of the hypothalamus and released into the circulation from the posterior lobe of the pituitary gland together with a C-terminal fragment of pro-vasopressin, known as copeptin. Additionally, vasopressinergic neurons project from the hypothalamus to the brainstem nuclei. Increased release of AVP into the circulation and elevated levels of its surrogate marker copeptin are found in pulmonary diseases, arterial hypertension, heart failure, obstructive sleep apnoea, severe infections, COVID-19 due to SARS-CoV-2 infection, and brain injuries. All these conditions are usually accompanied by respiratory disturbances. The main stimuli that trigger AVP release include hyperosmolality, hypovolemia, hypotension, hypoxia, hypoglycemia, strenuous exercise, and angiotensin II (Ang II) and the same stimuli are known to affect pulmonary ventilation. In this light, we hypothesize that increased AVP release and changes in ventilation are not coincidental, but that the neurohormone contributes to the regulation of the respiratory system by fine-tuning of breathing in order to restore homeostasis. We discuss evidence in support of this presumption. Specifically, vasopressinergic neurons innervate the brainstem nuclei involved in the control of respiration. Moreover, vasopressin V1a receptors (V1aRs) are expressed on neurons in the respiratory centers of the brainstem, in the circumventricular organs (CVOs) that lack a blood-brain barrier, and on the chemosensitive type I cells in the carotid bodies. Finally, peripheral and central administrations of AVP or antagonists of V1aRs increase/decrease phrenic nerve activity and pulmonary ventilation in a site-specific manner. Altogether, the findings discussed in this review strongly argue for the hypothesis that vasopressin affects ventilation both as a blood-borne neurohormone and as a neurotransmitter within the central nervous system.

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“…Regulation of different variables involve shared brainstem centers (90). For instance, a key common site of initial synapse formation for internal reflexes is the NTS, and a key common site of output to the sympathetic preganglionic neurons is the RVLM.…”

Section: R305mentioning

confidence: 99%

How does homeostasis happen? Integrative physiological, systems biological, and evolutionary perspectives

Goldstein

2019

American Journal of Physiology-Regulatory, Integrative and Comp

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Homeostasis is a founding principle of integrative physiology. In current systems biology, however, homeostasis seems almost invisible. Is homeostasis a key goal driving body processes, or is it an emergent mechanistic fact? In this perspective piece, I propose that the integrative physiological and systems biological viewpoints about homeostasis reflect different epistemologies, different philosophies of knowledge. Integrative physiology is concept driven. It attempts to explain biological phenomena by continuous formation of theories that experimentation or observation can test. In integrative physiology, “function” refers to goals or purposes. Systems biology is data driven. It explains biological phenomena in terms of “omics”–i.e., genomics, gene expression, epigenomics, proteomics, and metabolomics–it depicts the data in computer models of complex cascades or networks, and it makes predictions from the models. In systems biology, “function” refers more to mechanisms than to goals. The integrative physiologist emphasizes homeostasis of internal variables such as Pco2 and blood pressure. The systems biologist views these emphases as teleological and unparsimonious in that the “regulated variable” (e.g., arterial Pco2 and blood pressure) and the “regulator” (e.g., the “carbistat” and “barostat”) are unobservable constructs. The integrative physiologist views systems biological explanations as not really explanations but descriptions that cannot account for phenomena we humans believe exist, although they cannot be observed directly, such as feelings and, ultimately, the conscious mind. This essay reviews the history of the two epistemologies, emphasizing autonomic neuroscience. I predict rapprochement of integrative physiology with systems biology. The resolution will avoid teleological purposiveness, transcend pure mechanism, and incorporate adaptiveness in evolution, i.e., “Darwinian medicine.”

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Integration of hindbrain and carotid body mechanisms that control the autonomic response to cardiorespiratory and glucoprivic insults

Cited by 4 publications

References 96 publications

Repetitive hypoglycemia reduces activation of glucose-responsive neurons in C1 and C3 medullary brain regions to subsequent hypoglycemia

Repetitive hypoglycemia reduces activation of glucose-responsive neurons in C1 and C3 medullary brain regions to subsequent hypoglycemia

Vasopressin and Breathing: Review of Evidence for Respiratory Effects of the Antidiuretic Hormone

How does homeostasis happen? Integrative physiological, systems biological, and evolutionary perspectives

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