Ⅵ REVIEW ARTICLE David C. Warltier, M.D., Ph.D., Editor Anesthesiology 2007; 107:822–42 Copyright © 2007, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Nitric Oxide Involvement in the Effects of Anesthetic Agents Noboru Toda, M.D., Ph.D.,* Hiroshi Toda, M.D., Ph.D.,† Yoshio Hatano, M.D., Ph.D.‡ Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/107/5/822/365245/0000542-200711000-00020.pdf by guest on 28 September 2021 There has been an explosive increase in the amount of A detailed discussion about nitric oxide–morphine inter- interesting information about the physiologic and pathophysi- actions is beyond the scope of the current review and ologic roles of nitric oxide in cardiovascular, nervous, and must remain for a future review article. immune systems. The possible involvement of the nitric oxide– cyclic guanosine monophosphate pathway in the effects of an- Endothelium-derived relaxing factor (EDRF), discov- 1 esthetic agents has been the focus of many investigators. Relax- ered by Furchgott and Zawadzki, was determined to be ations of cerebral and peripheral arterial smooth muscle as well biochemically and functionally identical to nitric ox- as increases in cerebral and other regional blood flows induced ide.2–4 Introduction of nitric oxide synthase (NOS) in- by anesthetic agents are mediated mainly via nitric oxide re- hibitors5 accelerated the progress of investigations to leased from the endothelium and/or the nitrergic nerve and clarify the important roles of nitric oxide in the regula- also via prostaglandin I2 or endothelium-derived hyperpolariz- ing factor. Preconditioning with volatile anesthetics protects tion of not only cardiovascular functions but also central against ischemia-reperfusion–induced myocardial dysfunction and peripheral nerve functions and immune reactions. and cell death or neurotoxicity, possibly through nitric oxide Nitric oxide has beneficial–destructive duality; nitric ox- release. Inhibition of nitric oxide synthase decreases the anes- ide formed via constitutive NOS mainly has physiologi- thetic requirement. Involvement of nitric oxide in the effects of volatile, intravenous, and local anesthetics differs. This review cally pivotal functions as an endothelial messenger, neu- article includes a summary of information about the sites and rotransmitter, or neuromodulator, whereas nitric oxide mechanisms by which various anesthetic agents interact with formed in excess through inducible NOS is detrimental the nitric oxide–cyclic guanosine monophosphate system. 6 to cell viability. PGI2 (prostacyclin) synthesized from THIS review article covers the involvement of nitric arachidonic acid in the endothelial cells possesses a oxide, and also endothelium-derived hyperpolarizing fac- vasodilator action and an antiaggregatory property as nitric oxide does.7 There are evidences supporting the tor (EDHF) or prostaglandin I2 (PGI2), in the effects of anesthetic agents on regional and systemic circulation, hypothesis that vascular endothelial cells can liberate including the myocardium, and the central and periph- one or more active substances, other than nitric oxide eral nervous systems; and we will discuss the different and PGI2, that result in hyperpolarization of vascular effectiveness of volatile, intravenous, and local anes- smooth muscle cell membranes associated with muscu- 8 thetic agents in experimental mammals. Some informa- lar relaxation; therefore, it is called EDHF. tion regarding human materials is also included; how- Besides the major effects on the central nervous sys- ever, the available information is still insufficient to tem in eliciting unconsciousness, analgesia, and de- construct a clinically applicable hypothesis by extrapo- creased skeletal muscle tone, anesthetic agents exert a lating the data from experimental mammals to humans. variety of actions on the whole body, mainly on the cardiovascular and nervous systems. There is evidence that nitric oxide and other endothelium-derived vasodi- This article is featured in “This Month in Anesthesiology.” lating factors are involved in mechanisms underlying the ᭛ Please see this issue of ANESTHESIOLOGY, page 5A. action of anesthetic agents; i.e., contribution to vasodi- lator and hypotensive responses to anesthetics, benefi- * Professor Emeritus, Shiga University of Medical Science, Shiga, Japan; cial effects of anesthetic preconditioning against isch- Toyama Institute for Cardiovascular Pharmacology Research, Osaka, Japan. emic damage in the heart and brain, and involvement in † Head of Anesthesiology, Department of Anesthesiology, Kyoto Katsura Hospi- tal, Kyoto, Japan. ‡ Professor of Anesthesiology, Department of Anesthesiology, alterations of the minimum alveolar concentration for Wakayama Medical University, Wakayama, Japan. volatile anesthesia (MAC). Received from the Toyama Institute for Cardiovascular Pharmacology Research, Osaka, Japan. Submitted for publication March 22, 2007. Accepted for publication July 2, 2007. Support was provided solely from institutional and/or departmental Syntheses and Actions of Nitric Oxide and sources. Other Endothelium-derived Relaxing Factors David S. Warner, M.D., served as Section Editor for this article. Address correspondence to Dr. N. Toda: Toyama Institute for Cardiovascular Nitric Oxide Pharmacology Research, 7-13, 1-Chome, Azuchimachi, Chuo-ku, Osaka 541-0052, L Japan. [email protected]. This article may be accessed for Nitric oxide is produced when -arginine is trans- personal use at no charge through the Journal Web site, www.anesthesiology.org. formed to L-citrulline through catalysis by NOS in the Anesthesiology, V 107, No 5, Nov 2007 822 NITRIC OXIDE INVOLVED IN ANESTHETIC AGENT ACTIONS 823 Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/107/5/822/365245/0000542-200711000-00020.pdf by guest on 28 September 2021 Fig. 1. Schematic presentation of information pathways via nitric oxide (NO), prostaglandin I2 (PGI2), and endothelium-derived hyperpolarizing factor (EDHF) from endothelial cells or NO from nitrergic nerves to vascular smooth muscle cells. In the third square from the left (for endothelial nitric oxide synthase [eNOS]), the transmembrane influx of Ca2؉ and its mobilization from intracellular storage sites are elicited by activation of drug receptors (R), such as muscarinic, peptidergic (bradykinin and substance ␣ P), and 2-adrenergic receptors, located on the endothelial cell membrane or by mechanical stimuli such as shear stress. Shear 1177/1179 stress, bradykinin, or insulin induces the phosphorylation of Ser of eNOS through phosphatidylinositol-3 kinase (PI3K) and the downstream serine/threonine protein kinase Akt (protein kinase B), resulting in increased NO formation. This mechanism does (not require the increase in intracellular Ca2؉ for NO production. At the top right, nitrergic nerves (postganglionic parasympathetic innervating the vascular wall participate in maintaining vasodilatation in cerebral arteries that are scarce in adrenergic vasocon- strictor innervation and also contribute to functionally counteract the adrenergic vasoconstrictor nerves in peripheral blood vessels to maintain blood flow homeostasis. In the top left square, activation of receptors by agonists or mechanical stress applied to the 2؉ endothelial cell membrane leads to transmembrane Ca influx; the cations activate phospholipase A2 (PLA2) to form arachidonic acid (AA), thus increasing the PGI2 synthesis. PGI2 liberated from the endothelial cells binds to PGI2 (IP) receptors located in smooth muscle cell membranes, activates adenylyl cyclase (AC), and stimulates cyclic adenosine monophosphate (cAMP) production, resulting in vascular smooth muscle relaxation. Solid line denotes stimulation; dotted line denotes inhibition; R denotes receptive site for chemical or 2؉ ؍ 2؉ ؍ ؍ 2؉ mechanical stimuli; pool denotes Ca storage site. 7-NI 7-nitroindazol; ATP adenosine triphosphate; [Ca ]i intracellular Ca ؍ guanylyl cyclase; GTP ؍ cyclooxygenase; GC ؍ cyclic guanosine monophosphate; COX ؍ calmodulin; cGMP ؍ concentration; CaM -NG-nitro-L ؍ NG-nitro-L-arginine; L-NAME ؍ L-citrulline; L-NA ؍ .L-arginine; L-Citru ؍ .indomethacin; L-Arg ؍ guanosine triphosphate; IM ؍ *neuronal nitric oxide synthase; NOS ؍ methylene blue; nNOS ؍ NG-monomethyl-L-arginine; MB ؍ arginine methylester; L-NMMA ؍ ؍ ؍ ؍ ؊ ؍ activated nitric oxide synthase; O2 oxygen; O2 superoxide anion; oxyHb oxyhemoglobin; PDE-5 phosphodiesterase-5; PG-EP .superoxide dismutase ؍ phospholipids; SOD ؍ prostaglandin endoperoxide; PL presence of oxygen and a number of cofactors: reduced constitutively expressed but is induced mainly in macro- nicotinamide adenine dinucleotide phosphate, tetrahydro- phages with bacterial lipopolysaccharide and cytokines. biopterin, calmodulin, heme, flavin adenine dinucleotide, Nitric Oxide Derived from the Endothelium. En- and flavin mononucleotide. Ca2ϩ is required for the activa- dothelial NOS binds to caveolin 1 in the caveolae, mi- tion of neuronal NOS (nNOS, NOS I) and endothelial NOS crodomains of the plasma membrane. Caveolin 1 inhibits (eNOS, NOS III) but not inducible or immunologic NOS eNOS activity, and this interaction is regulated by Ca2ϩ/ (iNOS, NOS II). The nNOS, mostly a soluble enzyme, is calmodulin.11 eNOS intracellularly migrates in response constitutively expressed in the brain9 and peripheral to increased cytosolic Ca2ϩ in the presence of calmod- nerves. eNOS is also constitutively expressed mostly in ulin and