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The Human Carotid Body Expression of Oxygen Sensing and Signaling Genes of Relevance for Anesthesia

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The Human Carotid Body Expression of Oxygen Sensing and Signaling Genes of Relevance for Anesthesia PERIOPERATIVE MEDICINE Anesthesiology 2010; 113:1270–9 Copyright © 2010, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins The Human Carotid Body Expression of Oxygen Sensing and Signaling Genes of Relevance for Anesthesia Malin Jonsson Fagerlund, M.D., Ph.D.,* Jessica Kåhlin, M.D.,† Anette Ebberyd, B.M.A.,‡ Gunnar Schulte, Ph.D.,§ Souren Mkrtchian, M.D., Ph.D.,ʈ Lars I. Eriksson, M.D., Ph.D., F.R.C.A.# Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/113/6/1270/252613/0000542-201012000-00011.pdf by guest on 28 September 2021 ABSTRACT with DNA microarrays, real-time polymerase chain reaction, Background: Hypoxia is a common cause of adverse events and immunohistochemistry. in the postoperative period, where respiratory depression due Results: We found gene expression of the oxygen-sensing ϩ to residual effects of drugs used in anesthesia is an important pathway, heme oxygenase 2, and the K channels TASK ϩ underlying factor. General anesthetics and neuromuscular (TWIK-related acid sensitive K channel)-1 and BK (large- blocking agents reduce the human ventilatory response to conductance potassium channel). In addition, we show the hypoxia. Although the carotid body (CB) is the major oxygen expression of critical receptor subunits such as ␥-aminobu- ␣ ␤ ␥ sensor in humans, critical oxygen sensing and signaling path- tyric acid A ( 2, 3, and 2), nicotinic acetylcholine recep- ␣ ␣ ␤ ways have been investigated only in animals so far. Thus, the tors ( 3, 7, and 2), purinoceptors (A2A and P2X2), and aim of this study was to characterize the expression of key the dopamine D2 receptor. genes and localization of their products involved in the hu- Conclusions: In unique samples of the human CB, we here man oxygen sensing and signaling pathways with a focus on demonstrate presence of critical proteins in the oxygen-sens- receptor systems and ion channels of relevance in anesthesia. ing and signaling cascade. Our findings demonstrate similar- Methods: Six CBs were removed unilaterally from patients ities to, but also important differences from, established an- undergoing radical neck dissection. The gene expression and imal models. In addition, our work establishes an essential platform for studying the interaction between anesthetic cell-specific protein localization in the CBs were investigated drugs and human CB chemoreception. * Assistant Professor, † Resident, # Professor and Academic Chair, What We Already Know about This Topic Section for Anesthesiology and Intensive Care Medicine, Depart- ment of Physiology and Pharmacology, Karolinska Institutet, and ❖ Although molecular mechanisms of the oxygen-sensing ap- Department of Anesthesiology and Intensive Care Medicine, Karo- paratus in the carotid body have been partly probed in ani- linska University Hospital, Stockholm, Sweden. ‡ Clinical Labora- mals, the mechanisms in humans are unknown. tory Scientist, ʈ Associate Professor, Section for Anesthesiology and Intensive Care Medicine, § Associate Professor, Section for Receptor What This Article Tells Us That Is New Biology and Signaling, Department of Physiology and Pharmacol- ogy, Karolinska Institutet. ❖ Six carotid bodies were removed during radical neck dissec- tion and subjected to high-resolution gene analysis and Received from the Department of Physiology and Pharmacology, immunohistochemistry. Section for Anesthesiology and Intensive Care Medicine, Karolinska ❖ Institutet, and the Department of Anesthesiology and Intensive Care There are similarities but also key differences in genetic ex- Medicine, Karolinska University Hospital, Stockholm, Sweden. Sub- pression of putative components of oxygen sensing in human mitted for publication June 29, 2010. Accepted for publication Au- carotid body compared with that in other species. gust 23, 2010. Supported by the Stockholm County Council (Swe- den), the Swedish Research Council (Stockholm) Project nos. K2008-53X-13405-09-3 and K2008-68P-20810-01-4, and the Swedish Society of Medicine (Stockholm), Karolinska Institutet and Knut & XYGEN is an essential substrate for all mammalian Alice Wallenberg Foundation Grant no. KAW2008.0149. Drs. Fag- Ocells, and early detection of hypoxia is critical to pro- erlund and Kåhlin contributed equally to this work. Presented in tect organs and the whole body against cell damage and part at the Annual Meeting of the European Society of Anaesthesi- ology, Euroanaesthesia, Helsinki, Finland, June 12–15, 2010. death. The carotid body (CB) is the global oxygen sensor that Address correspondence to Dr. Fagerlund: Department of promptly regulates ventilation and cardiorespiratory reflexes Physiology and Pharmacology, Section for Anesthesiology and Intensive Care Medicine, Karolinska Institutet, SE-171 76 Stock- holm, Sweden. [email protected]. This article may ᭛ This article is featured in “This Month in Anesthesiology.” be accessed for personal use at no charge through the journal Please see this issue of ANESTHESIOLOGY, page 9A. website, www.Anesthesiology.org. 1270 Anesthesiology, V 113 • No 6 • December 2010 Human Carotid Body Key Proteins of O2 Chemoreception during acute hypoxia.1 Many drugs used in anesthesia de- Table 1. Patient Characteristics press regulation of breathing during acute hypoxia (e.g., Patient No. Age, yr ASA BMI propofol, halogenated inhaled general anesthetics, and neu- romuscular blocking agents [NMBAs]).2–5 Although such 1 67 1 25.6 agents clearly blunt the acute hypoxic ventilatory response 2 36 1 21.1 (HVR) in humans, the mechanism(s) by which they interfere 3 68 1 19.6 4 64 2 31.1 with oxygen sensing and signaling remains an enigma. 5 38 1 25.7 In brief, the acute HVR is triggered by stimulation of 6 56 1 23.5 peripheral chemoreceptor cells (type 1 cells) in the CB.1 The oxygen-sensing mechanism(s) in the CB is not fully under- ASA ϭ American Society of Anesthesiologists Physical Status Classification; BMI ϭ body mass index. stood but has been proposed to involve metabolic mitochon- Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/113/6/1270/252613/0000542-201012000-00011.pdf by guest on 28 September 2021 drial inhibition, production of oxygen radicals, inhibition of the hypoxia-induced factor pathway, or decreased carbon study after informed written consent. None of the patients monoxide production by heme oxygenase 2 (HO-2) associ- had received radiation or chemotherapy before surgery, none ϩ ated with the large-conductance potassium (BK) K chan- had a tumor involving the CB, and none was using nicotine. nel.6 Early events in oxygen sensing involve closure of oxy- Exclusion criteria were severe cardiopulmonary (New York ϩ gen-sensitive K channels in the CB type 1 cell, a subsequent Heart Association Functional Classification more than 2), membrane depolarization, and opening of voltage-depen- neurologic, or metabolic disease and smoking. Demographic ϩ ϩ dent Ca2 channels. The resultant Ca2 influx triggers re- data are presented in table 1. lease of neurotransmitters, with a subsequent increase of ac- During sevoflurane-narcotic based anesthesia with nor- tivity in the afferent carotid sinus nerve. This activates areas moxic and normocapnic mechanical ventilation (Aisys; GE in the brainstem responsible for regulation of breathing.1 Healthcare, Madison, WI), the CB was removed by the Among the multitude of transmitters released, acetylcholine head-and-neck surgeon after unilateral neck dissection. The and adenosine triphosphate (ATP) seem to be important CBs (weight range, 50–80 mg) were divided into pieces of excitatory transmitters, whereas dopamine and ␥-aminobu- equal size and immediately either frozen in liquid nitrogen tyric acid (GABA) have modulatory and inhibitory func- for RNA isolation or fixed in 4% paraformaldehyde at 4°C tions, respectively.6,7 General anesthetics and nondepolariz- for immunohistochemistry. ing NMBAs target ion channels such as GABAA receptors, ϩ nicotinic acetylcholine receptors (nAChRs), and leak K Total RNA Extraction and Purification channels.8–10 In addition, propofol and nondepolarizing Snap frozen pieces of CBs weighing ϳ20–35 mg were stored NMBAs blunt oxygen signaling in CB of many animal spe- at Ϫ80°C until RNA was prepared. For isolation of total cies, and the halogenated inhaled anesthetics halothane and RNA, samples were homogenized using a Potter-Elvehjem ϩ sevoflurane have a distinct action on K channels in the CB Teflon pestle homogenizer in 1 ml TRIzol® (Invitrogen, type 1 cells.11–14 Thus, drugs used in anesthesia have the Carlsbad, CA) and allowed to stand for 5 min at room tem- potential to target critical steps in global oxygen-sensing and perature. The homogenate was then mixed with 0.2 ml chlo- signaling pathways of the CB. Although components of the roform, vigorously shaken for 15 s, and incubated at room oxygen sensing and signaling pathways in experimental ani- temperature for 2–3 min. The mixture was centrifuged for 5 mals have been partially characterized, the pathways of the min at 12,000g at 4°C, the aqueous phase was transferred to human CB are at present unknown.1,6 a fresh microcentrifuge tube, and 1 volume of 70% ethanol Consequently, as a first step toward a better understand- was added. Thereafter, RNA was isolated using an RNeasy ing of these fundamental mechanisms, we here characterize kit (Invitrogen) according to the manufacturer’s recommen- components of the human oxygen-sensing and signaling dations. The yields of RNA were from 1 to 2 ␮g. All RNA pathways with a focus on GABAergic,
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