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Vasopressin: Mechanisms of Action on the Vasculature in Health and in Septic Shock

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Vasopressin: Mechanisms of Action on the Vasculature in Health and in Septic Shock Continuing Medical Education Article Vasopressin: Mechanisms of action on the vasculature in health and in septic shock Lucinda K. Barrett, MA, MBBS, MRCP; Mervyn Singer, MBBS, MD, FRCP; Lucie H. Clapp, PhD LEARNING OBJECTIVES On completion of this article, the reader should be able to: 1. Explain the effects of vasopressin on healthy patients. 2. Describe the effects of vasopressin in patients with septic shock. 3. Use this information in the clinical setting. Dr. Singer has disclosed that he is/was the recipient of grant/funds from The Medical Research Council UK and that he is a consultant for Ferring. Dr. Clapp has disclosed that she is recipient of grant funds from The Medical Research Council. Lippincott CME Institute, Inc., has identified and resolved all faculty conflicts of interest regarding this educational activity. Visit the Critical Care Medicine Web site (www.ccmjournal.org) for information on obtaining continuing medical education credit. Background: Vasopressin is essential for cardiovascular ho- in septic shock follows, with reference to relevant clinical, in vivo, meostasis, acting via the kidney to regulate water resorption, on the and in vitro experimental evidence. vasculature to regulate smooth muscle tone, and as a central neu- Data Source: Search of the PubMed database (keywords: vaso- rotransmitter, modulating brainstem autonomic function. Although it pressin and receptors and/or sepsis or septic shock) for articles is released in response to stress or shock states, a relative deficiency published in English before May 2006 and manual review of article of vasopressin has been found in prolonged vasodilatory shock, such bibliographies. as is seen in severe sepsis. In this circumstance, exogenous vaso- Data Synthesis and Conclusions: The pathophysiologic mecha- pressin has marked vasopressor effects, even at doses that would not nism underlying vasopressin hypersensitivity in septic shock is prob- affect blood pressure in healthy individuals. These two findings ably multifactorial. It is doubtful that this phenomenon is merely the provide the rationale for the use of vasopressin in the treatment of consequence of replacing a deficiency. Changes in vascular receptors septic shock. However, despite considerable research attention, the or their signaling and/or interactions between vasopressin, nitric mechanisms for vasopressin deficiency and hypersensitivity in vaso- oxide, and adenosine triphosphate-dependent potassium channels dilatory shock remain unclear. are likely to be relevant. Further translational research is required to Objective: To summarize vasopressin’s synthesis, physiologic improve our understanding and direct appropriate educated clinical roles, and regulation and then review the literature describing its use of vasopressin. (Crit Care Med 2007; 35:33–40) vascular receptors and downstream signaling pathways. A discus- KEY WORDS: vasopressin; septic shock; vasopressor agents; recep- sion of potential mechanisms underlying vasopressin hypersensitivity tors; nitric oxide; potassium channels asopressin (antidiuretic hor- migrate via the supraoptic-hypophyseal governed by changes in serum osmolarity mone) is a nonapeptide hor- tract to the posterior pituitary gland, (osmoregulation). This system is highly mone synthesized in the mag- where they are stored in neurosecretory sensitive, such that a small (2%) increase nocellular neurons of the vesicles (1). Under normal conditions, in osmolarity is reversed by the antidi- -pg/mL) in 5ف) Vparaventricular and supraoptic nuclei of circulating levels are maintained at uretic effect of a small the hypothalamus. Hormone precursors around 2 pg/mL (10Ϫ12 M) (1, 2). Only crease in vasopressin (2). In contrast, 10–20% of the hormone within the poste- baroregulation of vasopressin secretion rior pituitary can be rapidly released, and only plays a significant role in the context Clinical Research Training Fellow (LKB), Professor of with sustained stimulation this occurs at a of a Ͼ10% decrease in blood pressure. Intensive Care Medicine (MS), Professor of Vascular Phys- greatly reduced rate (1). Vasopressin is rap- Hormone levels can then increase more iology (LHC), Department of Medicine and Wolfson Insti- tute for Biomedical Research, University College London, idly metabolized by liver and kidney vaso- than ten-fold to help restore normoten- London, UK. pressinases and has a half-life of 10–35 sion, largely via vasoconstriction (2). Copyright © 2006 by the Society of Critical Care mins (1). Vasopressin release is affected by other Medicine and Lippincott Williams & Wilkins Regulation of vasopressin release is hormones. At low concentrations, cat- DOI: 10.1097/01.CCM.0000251127.45385.CD complex. In health, secretion is primarily echolamines tend to exert stimulatory ef- Crit Care Med 2007 Vol. 35, No. 1 33 ␣ fects via central 1 receptors but at higher levels may inhibit vasopressin re- ␣ ␤ lease via 2 and receptors (3, 4). Secre- tion of vasopressin also stimulates release of adrenocorticotropic hormone from the anterior pituitary, with consequent neg- ative feedback of glucocorticoids on the posterior pituitary (2). Additional factors are important in critical illness. Hypoxia and acidosis stimulate carotid body che- moreceptors to increase vasopressin re- lease (1). Furthermore, both endotoxin and cytokines enhance vasopressin pro- duction (2), whereas nitric oxide (NO) plays a mainly inhibitory neuromodulat- ing role on its secretion (5). The actions of vasopressin are medi- ated via G protein-coupled receptors, classified by virtue of their location and second messenger pathways into V1 (or V1a), V2, and V3 (formerly V1b) receptors (6). In addition, vasopressin has equal affinity with oxytocin for oxytocin recep- tors (OTRs) and may exert some of its actions via this route (7). ϩ Figure 1. A schematic showing the pathways of intracellular calcium (Ca2 ) elevation following the V1 Receptors (V1Rs). V1Rs are found binding of vasopressin (VP) to the V receptor (V R) on a vascular smooth muscle cell. The weighting mainly on vascular smooth muscle in the 1 1 of the black solid arrows demonstrates the relative importance of the different pathways. V1Rs are systemic, splanchnic, renal, and coronary coupled through Gq/11 to phospholipase C (PLC), which hydrolyzes phosphatidyl inositol bisphospho- circulations. They are coupled through nate (PIP2) to produce inositol triphosphate (IP3) and diacylglycerol (DAG). The latter, in turn, 2ϩ Gq/11 to phospholipase C (PLC), and their stimulates the activity of protein kinase C (PKC). A transient increase in intracellular Ca is produced activation produces vasoconstriction via by the action of IP3 on the sarcoplasmic reticulum, whereas a sustained increase is triggered by influx ϩ the elevation of intracellular calcium of extracellular Ca2 . Store-operated channels (SOCs), activated by intracellular store depletion, (Ca2ϩ)(Figs. 1 and 2). The emptying of appear to play a minor role in comparison to voltage-gated calcium channels (VGCCs) and receptor- stores within the sarcoplasmic reticulum operated channels (ROCs). VGCCs are opened by cell membrane depolarization, secondary to cation ϩ influx via ROCs and the PKC-mediated closure of adenosine triphosphate-sensitive potassium (K ) transiently increases cytoplasmic Ca2 , ATP channels. PKC can also open VGCCs directly. The opening of ROCs is G protein-dependent via PLC, whereas a sustained increase is produced with a downstream mechanism involving DAG and arachidonic acid (AA). They have significant 2ϩ by influx of extracellular Ca (8, 9). The permeability to Ca2ϩ, which is likely to contribute directly to contraction. pathways leading to vasopressin-induced extracellular calcium entry are complex (Fig. 1). Store-operated channels proba- brainstem (7). The latter mediate vaso- date, the best characterized role of the bly play a minor role compared with volt- pressinergic modulation of the autonomic V3R is in the secretion of adrenocortico- age-gated calcium channels and receptor- nervous system (15) and are responsible for tropic hormone, which appears to be me- operated channels (10, 11). Voltage-gated a baroreflex-mediated decrease in heart diated via the activation of PKC (7). calcium channels are activated indirectly rate, which precludes a pressor effect when Oxytocin Receptors (OTRs). Like by cell membrane depolarization or di- vasopressin acts on vascular smooth mus- V1Rs, OTRs are coupled to PLC, the me- rectly by protein kinase C (PKC) (12) cle in healthy people (16). tabolism of phosphoinositides, and the (Fig. 1). The opening of receptor-oper- V2 Receptors (V2Rs). V2Rs mediate the consequent elevation of intracellular cal- ated channels is G protein-dependent via antidiuretic actions of vasopressin within cium (7). In myometrial and mammary PLC and its downstream second messen- the kidney and are coupled through Gs to myoepithelial cells, OTR stimulation pro- gers, diacylglycerol and arachidonic acid adenylyl cyclase. Receptor stimulation duces smooth muscle contraction (7), (10, 13). Receptor-operated channels per- produces an increase in intracellular cy- and this may also occur in vascular mit nonselective cation influx, promoting clic adenosine monophosphate (cAMP), smooth muscle (17, 18) (Fig. 2). In addi- membrane depolarization, and a significant activation of protein kinase A, and the tion, OTRs are highly expressed in the Ca2ϩ entry, which contributes directly to insertion of water channels (aquaporins) vascular endothelium (19), where an in- contraction (13).
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