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 negative 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 release (1). Furthermore, both endotoxin and cytokines enhance vasopressin production (2), whereas nitric oxide (NO) plays a mainly inhibitory neuromodulat- ing role on its secretion (5). The actions of vasopressin are mediated 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 receptors (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). In addition to its effects into the luminal membranes of renal col- crease in intracellular Ca2ϩ activates con- on calcium influx, V1R stimulation may lecting duct cells (2, 7). As discussed in a stitutive endothelial NO synthase to re- sensitize the contractile apparatus to the later paragraph, there is ongoing debate lease NO and produce vasorelaxation (7) effect of calcium via the inhibition of myo- regarding the expression of V2Rs in the (Fig. 2). The lack of pressor response ob- sin light chain phosphatase by PKC (14) vasculature. served with oxytocin infusions in obstet-

(Fig. 2). V3 Receptors (V3Rs). V3Rs are found in rical practice may be consequent to the V1Rs are also found on platelets, on the anterior pituitary and are coupled to opposing effects of OTR stimulation on renal collecting duct cells, and in the various second messenger systems. To endothelial and smooth muscle cells.

34 Crit Care Med 2007 Vol. 35, No. 1 fection (31). Shock states generally trigger sympathetic and renin-angiotensin system activation and hence profound pe- ripheral vasoconstriction. In septic shock, however, vascular smooth muscle shows a decreased ability to contract, and the concomitant hypotension may be refractory to standard catecholamine vasopressor therapy. Although sepsis is the most common cause of so-called vasodilatory shock, it is also the ﬁnal common pathway for long-lasting and severe shock of any cause (32). The pathogenesis of vasodilatory shock is multifactorial. Increased NO, consequent to the activation of inducible NO synthase (iNOS), is a major contrib- utor to vasodilation, acting both directly and via cyclic guanosine monophosphate to lower intracellular calcium levels, decrease myosin light chain phosphoryla-

tion, and activate calcium-sensitive (KCa) Figure 2. Interplay between an endothelial and a vascular smooth muscle cell showing the mecha- and adenosine triphosphate-sensitive nisms by which vasopressin may produce vasoconstriction and/or vasodilation. Vascular smooth ϩ 2ϩ (KATP)K channels (32). Under physio- muscle V1 receptor (V1R) stimulation produces an elevation of intracellular calcium (Ca ). Smooth muscle oxytocin receptors (OTRs) are similarly coupled to phospholipase C (PLC) and its downstream logic conditions, KATP channels have low- second messenger pathways. Ca2ϩ binds to calmodulin and activates myosin light chain kinase level activity and play a minor role in blood

(MLCK). This enzyme catalyzes the phosphorylation (Pi) of myosin light chains (MLC), facilitating the pressure control (33, 34). In vasodilatory interaction between myosin and actin, which produces muscle contraction. V2 receptor (V2R) actions shock, however, these channels are per- are mediated via adenylate cyclase (AC) and, if present on vascular smooth muscle, could produce sistently open with consequent vascular vasorelaxation via a cyclic adenosine monophosphate (cAMP)-mediated decrease in intracellular Ca2ϩ. smooth muscle hyperpolarization and de- 2ϩ 2ϩ V1R activation may also enhance the response of the contractile apparatus to the effect of Ca via the creased Ca entry via voltage-gated cal- inhibition of myosin light chain phosphatase (Ca2ϩ sensitization). OTRs are highly expressed in the 2ϩ cium channels. This contributes to both vascular endothelium, where an increase in intracellular Ca activates constitutive endothelial nitric hypotension and hyporesponsiveness to oxide synthase (eNOS) to release nitric oxide (NO). There is experimental evidence to suggest the catecholamines (35–37). In addition to the existence of endothelial V1Rs and V2Rs. Stimulation of either subtype would activate eNOS, the former via calcium-calmodulin and the latter via an elevation in cAMP. Endothelial-derived NO causes effect of elevated NO, persistent KATP acti- vascular smooth muscle relaxation by a number of different pathways that are not detailed here. vation may result from tissue hypoxia, acidosis, reduced ATP, and changes in calcito- nin gene-related peptide, adenosine, and

Vasopressin produces vasodilation in chain reaction has demonstrated V2Rex- atrial natriuretic factor levels (34). A third some vascular beds, but the receptor sub- pression on cultured human lung endothe- factor is adrenoceptor desensitization and type responsible is uncertain, may vary lial cells and in heart, spleen, and lung down-regulation due to high circulating between blood vessels, and may depend whole tissue specimens (24). Use of a selec- levels of catecholamines (38, 39). on hormone concentration. The recep- tive V2R radioligand to demonstrate bind- The finding that patients with severe, tors mediating this effect may be situated ing to either vascular smooth muscle or refractory septic shock were exquisitely on endothelial or smooth muscle cells or endothelium in the rat, however, has been sensitive to the pressor effects of exoge- both. V2Rs on vascular smooth muscle unsuccessful (25). Ex vivo studies support nous vasopressin led to the investigation could produce vasorelaxation via a cAMP- an endothelium-dependent mechanism for of its endogenous profile (40). In acute mediated drop in intracellular calcium; vasopressin-induced vasodilation, but the septic shock, an early increase (approxi- alternatively, generation of cAMP in the effect of selective V2 agonists on relaxed mately ten-fold) in plasma vasopressin endothelium would trigger NO liberation arterial preparations has been variable (26– occurs in both patients (41) and animal Ն via endothelial NO synthase (Fig. 2). In- 30). Furthermore, endothelial V1Rs (28, models (42, 43). When prolonged ( 24 fusion of the V2 agonist, DDAVP, in 29) or OTRs (19) coupled to endothelial hrs), however, levels fall back toward anephric dogs elevated levels of plasma NO synthase activation could also ac- baseline (40, 41), a pattern mimicking cAMP coincident with a decrease in pe- count for vasopressin-mediated vasore- that observed for other hormones in ad- ripheral vascular tone, supporting the ex- laxation (Fig. 2). vanced critical illness (44). Hence, a rel- istence of extrarenal V2Rs (20). In healthy ative deficiency of vasopressin may also humans, high-dose vasopressin decreased Vasopressin in Septic Shock be crucial to the altered functional status forearm vascular resistance in a V2R- and of vascular smooth muscle. Indeed, in NO-dependent manner (21, 22). This va- Septic shock describes organ dysfunc- endotoxic models, V1R blockade wors- sodilation was not seen in patients with tion and hypotension unresponsive to ened hypotension (45), whereas survival nephrogenic diabetes insipidus secondary fluid resuscitation following a systemic was decreased in vasopressin-deficient toaV2R defect (23). Real-time polymerase inflammatory response syndrome to in- Brattleboro rats (46).

Crit Care Med 2007 Vol. 35, No. 1 35 Several animal models of septic shock have demonstrated hypersensitivity to vasopressin. In anesthetized endotoxic rats, a heightened contractile response of cre- master muscle microvessels to topical vasopressin was coincident to hyporeactivity to norepinephrine (62, 63). In our laboratory’s conscious, fluid-resuscitated model of rat fecal peritonitis (64), septic animals show a marked pressor response to terlipressin 24 hrs postinsult that is not seen in paired sham controls (65). Hypersensitivity to terlipressin was also seen in conscious ewes after 16 hrs of endotoxemia (66). Other in vivo setups have, however, produced discordant results (67–69), most likely related to the wide experimental variation in terms of duration, insult, severity, and fluid resuscitation. Although ex vivo reproduction of the vascular hyporeactivity to catecholamines is well described in septic models (70–72), there has been relatively little work exam- Figure 3. A schematic showing the potential mechanisms of hypersensitivity to vasopressin in septic ining vascular reactivity to vasopressin. shock at the level of a vascular smooth muscle cell. A further possibility not shown here is altered One study showed increased potency of va- baroreflex sensitivity consequent to autonomic dysfunction. OTR, oxytocin receptor; PLC, phospholipase C; eNOS, endothelial nitric oxide synthase; iNOS, inducible nitric oxide synthase; NO, nitric sopressin to constrict isolated mesenteric vessels from endotoxemic compared with oxide; KATP, adenosine triphosphate-sensitive potassium channel; HPA, hypothalamic-pituitary- adrenal; ET-1, endothelin-1; TXA2, thromboxane A2; V1,V1 vasopressin receptor; V2,V2 vasopressin control rats (73). In contrast, attenuated ␣ ␣ receptor; 1, 1 adrenoceptor. responses to vasopressin were observed in human gastroepiploic arteries after endotoxin treatment, but vasopressin signifi- Inappropriately low hormone levels teristic of the syndrome of inappropriate cantly enhanced norepinephrine-induced are not explained by increased vasopres- antidiuretic hormone. Landry and col- contractions in the same tissue (74). De- sin breakdown but may be caused by de- leagues (56) reported marked pressor creased sensitivity to both vasopressin pletion of neurohypophyseal stores or in- sensitivity to a low dose of vasopressin in and norepinephrine was found in isolated hibition of synthesis or release (47). five patients with sepsis-related refractory rat mesenteric arteries pretreated with an Either osmoregulation or baroregulation hypotension. The pressor effect occurred NO donor to simulate septic shock (75). may be abnormal, and baroreflex dys- within minutes and enabled catechol- function could underlie the apparent loss amines to be discontinued. Our group has MECHANISMS UNDERLYING of correlation between blood pressure published comparable results in a cohort VASOPRESSIN and vasopressin levels in septic shock of eight similar patients in whom terlip- HYPERSENSITIVITY (48). Impaired vasopressin release has been ressin, a long-acting synthetic vasopressin documented in patients with autonomic in- analogue, was administered (57). Despite These are summarized in Figure 3. sufficiency (49, 50), a phenomenon well an increasing number of related studies, recognized in sepsis (51). Elevated levels of most have only included small numbers Interaction With Other Factors NO may contribute to autonomic dysfunc- of patients and have been retrospective or Contributing to Vasodilatory tion (52) and have direct inhibitory effects nonrandomized (58). Ongoing is a large, Shock on vasopressin secretion (5). Sustained elevation of hormone levels following endo- multiple-center Canadian trial of vaso- Nitric Oxide. As discussed previously, toxin challenge in mice was seen in iNOS pressin vs. norepinephrine in septic elevated levels of NO in septic shock may knockouts or after pharmacologic NO inhi- shock (VASST), which will examine 28- contribute to relative vasopressin defi- bition (53–55). day mortality as the primary end point. ciency. Another consideration is a possi- Current consensus opinion is that low- ble reciprocal negative effect of vasopres- EVIDENCE FOR rate constant infusion (0.01–0.04 units/ sin on the NO cascade. Vasopressin HYPERSENSITIVITY TO min) of vasopressin is preferable to a inhibited interleukin-1 stimulated iNOS higher, blood pressure-titrated dose if VASOPRESSIN IN SEPTIC messenger RNA expression and nitrite coronary, mesenteric, and skin ischemias SHOCK and cyclic guanosine monophosphate are to be avoided (59, 60). There is in- production in cultured rat vascular Exogenous administration of vaso- creasing evidence to suggest neutral or smooth muscle cells (76). Basal NO pro- pressin in health does not elevate blood beneficial effects on renal blood flow and duction was unaltered, suggesting an ef- pressure, and hypertension is not charac- urine output at these low doses (58, 61). fect specific to iNOS and hence states of

36 Crit Care Med 2007 Vol. 35, No. 1 inflammatory activation. The hypothesis tions of vasopressin that do not apprecia- Another group reported a cytokine- that heightened sensitivity to exogenous bly constrict blood vessels alone (87). mediated decrease in V1Rs in liver, lung, vasopressin in septic shock may be con- Several possible explanations may un- kidney, and heart tissue isolated from en- sequent to iNOS inhibition is further sup- derlie this interaction. Norepinephrine dotoxic rats exposed for a similar period ␣ ported by the findings of an in vivo study produces its vasoconstrictive effect via 1 (93). This model was not fluid resusci- where administration of terlipressin to adrenoceptors which, like V1Rs, are cou- tated and did not demonstrate hypersen- endotoxic rats resulted in recovery of arte- pled via Gq/11 proteins to PLC. Norepi- sitivity to in vivo administration of a va- rial blood pressure associated with de- nephrine-induced contractions appear sopressin agonist. Comparable results creased iNOS expression in isolated aortic more dependent on release of intracellu- were seen in nonshocked rats who re- tissue (77). However, no decrease in serum lar calcium stores than influx of extracel- ceived continuous endotoxin infusion for nitrite/nitrate concentrations was demon- lular calcium, whereas the opposite ap- 30 hrs (94). Further studies are required strated in patients with vasodilatory shock plies for vasopressin (89). Thus, the to examine changes in receptor binding after vasopressin infusion (78). utilization of different calcium pathways in tissues from models more representa- may in part explain the synergism be- tive of human septic shock. KATP Channels. In septic shock KATP channels are persistently open, resulting tween the two agonists. Indeed, vasopres- V2 and Oxytocin Receptors. Whereas in a sustained hyperpolarized state and sin potentiation of adrenergic contrac- vasorelaxation can be mediated via both vasorelaxation. Inhibition of these chan- tion in isolated rat mesenteric arteries V2Rs and OTRs, changes in the expression nels could therefore help to restore nor- was blocked by both a V1R antagonist (74, or function of these receptors in sepsis mal vascular reactivity (37, 79). In vitro 87) and the voltage-gated calcium chan- remain unknown. Increasing availability work in cultured porcine vascular smooth nel blocker nifedipine (87). Alternatively, of specific agonists and antagonists now muscle cells and isolated cardiac myo- vasopressin may act via PKC and/or Rho- makes this a realistic proposition. V2R cytes has demonstrated the ability of va- associated kinase to inhibit myosin light recycling and resensitization are slow chain phosphatase, thereby sensitizing compared with V1Rs (6, 7). This may well sopressin to close KATP channels (80, 81). This effect was blocked by selective inhi- the contractile apparatus to the calcium be of relevance in the context of exoge- ␣ bition of PKC (81), which may act by increase produced by 1 adrenoceptor nous vasopressin administration and direct phosphorylation of the channel stimulation (14). Cross-regulation may could be one explanation for the observa- also occur at the level of the receptors. In tion that rebound hypotension on cessa- (82) or by increasing sarcolemmal ATP a cell line, V R activation nonreciprocally tion of vasopressin treatment in septic (81). Other non-PKC-mediated mecha- 2 inhibited adrenoceptor internalization shock is often prevented with the use of nisms are also possible. An increase in (90). The proposed mechanism is via al- terlipressin (57, 95), an analogue with intracellular calcium evoked by V R stim- 1 tered ␤-arrestin function; this protein greater selectivity for V Rs over V Rs (2.2 ulation could activate the calcium- 1 2 normally acts by binding to activated G vs. 1) (57, 96). dependent phosphatase, calcineurin, to protein-coupled receptors and effecting promote channel inhibition (79, 83). In their removal from the cell membrane. addition, calcineurin regulates gene tran- Autonomic Nervous System scription via the nuclear transcription Dysfunction factor nuclear factor of activated T cells; Changes in Vasopressin Receptor Behavior Vasopressin release is under the con- this in turn may down-regulate genes en- trol of the autonomic nervous system, coding KATP channel subunits, as has The opposing effects of vasopressin on with baro- and chemoreceptor afferents been shown for delayed rectifier potas- vascular tissue are consequent to the projecting to the brainstem and efferents sium channels (84). stimulation of different vasopressin re- from the brainstem to the paraventricu- Catecholamine Sensitivity. Clinical ceptor subtypes located on smooth mus- lar and supraoptic (3). By virtue of its experience with vasopressin and terlip- cle and/or endothelial cells. Differential neurotransmitter role, autonomic ner- ressin in patients with refractory septic changes in the regulation of these sub- vous system output is also modulated by shock suggests that vasopressin and ter- types could therefore explain the hyper- vasopressin (15). Therefore, the auto- lipressin restore vascular reactivity to sensitivity seen in septic shock. nomic and vasopressinergic system ab- both endogenous and exogenous cat- V1 Receptors. In contrast to high nor- normalities seen in sepsis may well be echolamines (56, 57, 85). In vivo poten- ␣ epinephrine levels and the resultant 1 related. Further complexity is added by tiation of the vasoconstrictor actions of receptor changes, relatively low circulat- the apparent negative correlation be- endogenous norepinephrine by physio- ing concentrations of vasopressin in pro- tween NO levels and sympathetic cardio- logic doses of exogenous vasopressin was longed septic shock would leave V1Rs vascular output (52, 97) and the known first reported Ͼ40 yrs ago (86). Parallel available for occupancy by exogenous interactions between vasopressin and NO ex vivo studies with rat aortic strips sug- hormone and decrease the endogenous described previously. In patients who gested a direct vascular rather than cen- stimulus for receptor desensitization (6, died from septic shock, iNOS expression tral mechanism of vasopressin action 32). Sepsis may also induce specific was linked to apoptosis in the paraven- (86). This potentiation has been con- changes in receptor populations. Endo- tricular and supraoptic nuclei (52). Pri- firmed in rat and human resistance arter- toxin can alter receptor function directly mary autonomic failure is associated with ies, seen in both normal vessels (87, 88) (91) or indirectly via cytokines, NO, and hypersensitivity to vasopressin’s pressor and those exposed to experimental sepsis PKC. No change in either the number or effects (98) as well as with abnormalities

(74, 75). Similarly, constriction evoked afﬁnity of V1Rs was seen in cultured aor- of its release (49). The former has also by stimulation of periarterial nerves is tic smooth muscle cells exposed to lipo- been reported in dogs with baroreceptor also enhanced and observed at concentra- polysaccharide for 24 hrs, however (92). denervation (99). Moreover, cirrhotic pa-

Crit Care Med 2007 Vol. 35, No. 1 37 tients show an abnormally prolonged CONCLUSIONS 8. Ruegg UT, Wallnofer A, Weir S, et al: blood pressure response to vasopressin, Receptor-operated calcium-permeable and this has been ascribed to abnormal Understanding the pathogenesis and channels in vascular smooth muscle. autonomic cardiovascular regulation pathophysiology of septic shock is chal- J Cardiovasc Pharmacol 1989; 14(Suppl (100). Vasopressin administration in sep- lenging. Reviewing the literature relevant 6):S49–S58 9. Nakajima T, Hazama H, Hamada E, et al: tic shock does not produce the degree of to vasopressin hypersensitivity shows that this particular area is no exception. Endothelin-1 and vasopressin activate bradycardia seen in normal individuals Ca(2ϩ)-permeable non-selective cation (40), suggesting impairment of normal The relationship between relative deficiency of endogenous vasopressin and channels in aortic smooth muscle cells: baroreflexes. Mechanism of receptor-mediated Ca2ϩ in- heightened sensitivity to its exogenous flux. J Mol Cell Cardiol 1996; 28:707–722 administration is not straightforward. 10. Broad LM, Cannon TR, Taylor CW: A non- Interaction With Other Recent work has found the circulating Vasoconstrictors capacitative pathway activated by arachi- hormone concentrations achieved with donic acid is the major Ca2ϩ entry mech- Elevated levels of endothelin-1 and vasopressin treatment to be supraphysi- anism in rat A7r5 smooth muscle cells ologic (Ͼ100 pg/mL), despite “low-dose” stimulated with low concentrations of vaso- thromboxane A2 are found in septic shock and contribute to the heterogeneity in regimens, and that pressor response is pressin. J Physiol 1999; 517:121–134 independent of baseline hormone levels 11. Katori E, Ohta T, Nakazato Y, et al: Vaso- tone observed across different vascular pressin-induced contraction in the rat basi- beds (101). Vasopressin administration (109). The explanation behind this complex vasopressinergic system dysfunction lar artery in vitro. Eur J Pharmacol 2001; may increase the synthesis of these vaso- 416:113–121 is likely to be multifactorial, and hence constrictors. In vitro work with human 12. Beech DJ: Actions of neurotransmitters and many possibilities exist for further inves- platelets showed that V1R stimulation ac- other messengers on Ca2ϩ channels and tivates not only PLC but also phospho- tigation. Ideally, an in vivo model truly Kϩ channels in smooth muscle cells. Phar- representative of prolonged, severe septic macol Ther 1997; 73:91–119 lipase A2, resulting in arachidonic acid metabolism and thromboxane production shock is required to evaluate temporal 13. Large WA: Receptor-operated Ca2(ϩ)- (102). In cultured endothelial cells, vaso- changes in vascular reactivity and endo- permeable nonselective cation channels in pressin enhanced both preproendothe- crine and autonomic function. 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