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Cardiovascular Research 2006 72(2):220-230; doi:10.1016/j.cardiores.2006.07.011
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Copyright © 2006, European Society of Cardiology

Role of KATP channels in sepsis

James F. Buckleya,b, Mervyn Singerb and Lucie H. Clappa,*

aBritish Heart Foundation Laboratories and Bloomsbury Institute for Intensive Care Medicine, UK
bDepartment of Medicine, University College London, 5, University Street, London, WC1E 6JF, UK

* Corresponding author. BHF Laboratories, Department of Medicine, 4th Floor Rayne Building, University College, 5 University Street, London WC1E 6JF, UK. Tel.: +44 20 7679 6180; fax: +44 20 7679 6250. Email address: l.clapp{at}ucl.ac.uk

Received 17 May 2006; revised 21 June 2006; accepted 18 July 2006


   Abstract
Top
 Abstract
1. Pathophysiology of septic...
 2. KATP channel structure...
 3. KATP channels and...
 4. What influences KATP...
 References
 
Sepsis is an infection-induced inflammatory syndrome responsible for ~10% of all deaths worldwide. While pathophysiological mechanisms remain to be fully unravelled, new insights and discoveries are yielding significant improvements in outcome, particularly in the high mortality conditions of shock and multi-organ failure. One potential target is the ATP-sensitive potassium (KATP) channel, an ion channel critical to the cardiovascular stress response. Excessive activation of the vascular channel is now recognised as a major cause of hypotension and vascular hyporesponsiveness to catecholamines in septic shock. Some researchers advocate therapeutic blockade of these channels; however, outside the vasculature, channel opening may actually represent a protective mechanism against cellular damage. In this review we critically examine the role of the KATP channel in sepsis.

KEYWORDS K-ATP channel; Sepsis; Septic shock; Vascular hyporeactivity; Multi-organ failure; Mitochondria; Insulin


   1. Pathophysiology of septic shock and multi-organ failure
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 Abstract
 1. Pathophysiology of septic...
2. KATP channel structure...
 3. KATP channels and...
 4. What influences KATP...
 References
 
Ill-defined genetic and cellular factors enable infectious insults to trigger an exaggerated and poorly regulated systemic inflammatory response. Components of the micro-organism bind to membrane-bound and soluble proteins within plasma, activating white cells, endothelium, platelets and coagulation pathways (reviewed in Refs [1–3]). Binding of pathogen-associated molecular patterns (cell wall constituents, toxins, superantigens and bacterial DNA) to Toll-like receptors and other recognition receptors activate nuclear transcription factors such as NF-{kappa}B [2,3]. These upregulate expression of genes encoding for pro-inflammatory mediators such as the cytokines, tumor necrosis factor alpha (TNF{alpha}) and interleukins (IL-1 and IL-6) and enzymes like inducible nitric oxide synthase (iNOS) and cyclo-oxygenase-2 (COX-2) [3]. Stimulation of the arachidonic acid cascade within endothelial cells generates pro-inflammatory prostaglandins, thromboxanes and leukotrienes, while activated neutrophils produce and release large quantities of proteases, hydrogen peroxide, and reactive oxygen species [2,4]. The net result is increased vascular permeability, with enhanced passage of fluid, plasma proteins and activated neutrophils to extravascular compartments, microcoagulopathy and alterations in microvascular tone. Synergism between pro-inflammatory mediators and tissue hypoxia consequent to hypovolaemia, interstitial oedema and blood flow redistribution will result in decreased mitochondrial energy production and a metabolic shutdown which becomes clinically apparent as organ dysfunction [1,4].

Sepsis affects, to a greater or lesser degree, every major organ within the body, potentially leading to their failure. The most severe cardiovascular manifestation is septic shock, a condition of perfusion abnormalities in conjunction with hypotension unresponsive to adequate fluid resuscitation. This results from a combination of excessive vasodilatation, vascular hyporeactivity (i.e. decreased responsiveness to catecholamines) and variable degrees of myocardial depression [1,2]. Mechanisms implicated in the development of vascular hyporeactivity include the nitric oxide (NO) pathway [5], excessive activation of potassium channels [6] and inappropriately low circulating levels of vasopressin [7]. Large dose catecholamine infusions can often be significantly reduced or even stopped after administering a NO synthase (NOS) inhibitor [5,8] or vasopressin [7,9]. Their actions are likely, at least in part, to result from closure of the vascular smooth muscle KATP channel.


   2. KATP channel structure and function
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 Abstract
 1. Pathophysiology of septic...
 2. KATP channel structure...
3. KATP channels and...
 4. What influences KATP...
 References
 
2.1. What is a K+ channel?
Potassium (K+) channels are membrane-spanning proteins that selectively allow movement of K+ ions across cells through a water-filled permeation pathway (pore). A gating mechanism (driven by a voltage or ligand binding) switches the channel between open and closed conformations. Normally channel opening at the plasma membrane promotes K+ loss from the cell, resulting in membrane hyperpolarisation, while in mitochondrial membranes this produces depolarisation. Key roles for K+ channels include maintenance of cellular resting membrane potential, regulation of neuronal excitability, neurotransmitter release, control of heart rate and smooth muscle tone, hormone secretion and epithelial electrolyte transport. Several hundred genes encoding for K+ channels have been identified and these broadly fall into three families; voltage-gated (including Kv and calcium-activated), inward rectifiers (Kir1-7.0) and twin pore K+ channels [10].

2.2. Basic channel characteristics
The KATP channel is an ubiquitously expressed protein (Table 1) with the particular characteristic of being blocked by intracellular ATP. In most tissues, inhibition by ATP occurs at micromolar concentrations but as cells usually contain millimolar ATP, channel openings will be rare. In contrast, nucleotide diphosphates (NDPs) such as adenosine diphosphate (ADP) activate the channel. Thus the ATP/NDP ratio is one of the major factors determining absolute channel activity [11–13]. These channel characteristics enable energy status within the cell to be directly linked to changes in membrane potential. During severe metabolic stress, ATP levels fall and NDP levels rise, thereby promoting substantial channel opening under these conditions. However, KATP channels do not simply respond to cell metabolism; other factors, including kinases, phosphatases, G-proteins and phospholipids regulate basal channel activity (Fig. 1). KATP channels can also be regulated both in vitro [14,15] and in vivo [16] through the Ca2+-dependent phosphatase, calcineurin, which indirectly regulates channel activity through an interaction with cyclic AMP-dependent protein kinase (PKA) [15]. This allows the channel to sense changes in intracellular Ca2+, being activated at resting levels and inhibited by high micromolar levels [14].


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  		Table 1 Molecular structure, pharmacology and function of KATP channels

 

Figure 1
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  		Fig. 1 Basic characteristics of KATP channels. Diagram illustrating factors that regulate the channel. PIP2: phosphatidylinositol-4,5-bisphosphate, KCOs: potassium channel openers, PKA: protein kinase A, Kir: inward rectifier subunit, SUR: sulphonylurea receptor subunit.

 
2.3. Channel structure
The KATP channel is a complex of at least two proteins: (i) the sulphonylurea receptor (SUR), and (ii) a pore-forming subunit belonging to the Kir6.0 family [11–13]. The stoichiometry consists of a tetramer of Kir6.0 subunits, which form the K+ selective pore-forming subunit, surrounded by four SUR proteins. These subunits have distinct functions. The SUR has high affinity binding sites for both sulphonylureas and K+ channel openers (KCOs) and has nucleotide (e.g. ADP) binding sites [11,12]. On the other hand, the pore-forming subunit controls the magnitude of K+ flow through the channel and is the site to which ATP binds to inhibit the channel. In addition, it possess low affinity binding sites for sulphonylureas and other types of channel inhibitors [11]. However, differing combinations of pore-forming and SUR subunits confer tissue-specific characteristics of the channel in the plasma membrane; the identity of KATP (mitoKATP) channels found in the inner mitochondrial membrane of different cell types is unknown (Table 1). Of note, the vascular smooth muscle KATP channel (synonymous with the KNDP channel) differs from the stereotypical KATP channel by being relatively insensitive to ATP. However, it is still activated by NDPs and inhibited by the sulphonylurea agent, glibenclamide (known in North America as glyburide) [13]. Importantly, key metabolically active proteins, including glycolytic enzymes involved in ATP production, exist in a macromolecular complex with the KATP channel and appear crucial in maintaining a high ATP/ADP ratio in the vicinity of the channel [17,18].

2.4. Physiological roles
The best characterised role of the KATP channel is to control insulin release from pancreatic β cells. During fasting, KATP channels are kept open by a low blood glucose (2–4 mmol/l). After a meal, glucose levels increase, causing intracellular ATP to rise, resulting in KATP channel closure and depolarization of the β cell membrane. This, in turn, opens voltage-gated Ca2+ channels, allowing Ca2+ to enter the cell. This triggers exocytosis of insulin-containing granules, thereby stimulating insulin release (reviewed in Ref. [12]).

KATP channels located in the hypothalamus are also involved in regulating glucose homeostasis. Glucose-sensing neurones in the ventromedial hypothalamus respond to hyperglycaemia by increasing their firing rate, reducing glucagon secretion and thus lowering glucose [12,19]. Such regulation is mimicked by sulphonylureas and is impaired in Kir6.2 knockout mice, strongly suggesting a link between KATP channels and the hypothalamic glucose-sensing mechanism, akin to that seen in pancreatic β cells [12]. KATP channels also regulate glucose uptake in skeletal muscle; this mechanism is proposed to underlie glibenclamide-stimulated glucose uptake [12,13]. Thus KATP channels from different tissues are involved in controlling glucose homeostasis in a co-ordinated manner [19].

In vascular smooth muscle, KATP channels contribute to the maintenance of resting membrane potential and local blood flow [13,20]. Such evidence is based upon observing significant effects of glibenclamide on vascular resistance, blood vessel diameter and membrane potential (Table 1). KATP channels influence vascular tone because of the steep relationship between membrane potential and Ca2+ influx. A small depolarisation (3 mV) can generate large (two-fold) changes in Ca2+ influx through voltage-dependent Ca2+ channels [20]. This, in turn, promotes contraction of the vascular smooth muscle cell. The extent to which KATP channels regulate systemic blood pressure under physiological conditions is unclear. Glibenclamide had little effect on blood pressure in normal animals [21–23], though the vascular selective inhibitor, PNU-37883A was able to elevate blood pressure, albeit more in dogs than rats [24]. These differences could reflect glibenclamide's ability to block all KATP channel subtypes in vivo but also oppose the circulating effects of thromboxane, being an antagonist of its receptor [25]. Consistent with a role for this channel in regulating blood pressure, SUR2 was reported to be a susceptibility gene for essential hypertension in humans [26] and mice lacking SUR2 develop hypertension and coronary vasospasm [12]. Hypertension could also potentially result from effects outside the vasculature, since both SUR2B and the Kir6.1 subunit are widely expressed throughout the body [27].

2.5. Hormonal regulation
It is well established that vasoactive substances modulate KATP channel activity (Table 1 and Fig. 2). Vasodilators elevating cyclic AMP, including calcitonin gene-related peptide (CGRP), adenosine and prostacyclin, activate KATP currents and produce glibenclamide-sensitive relaxation and hypotension [20,28]. Channel activation involves PKA [13,20] and the co-ordinated phosphorylation of sites located on both SUR2B and Kir6.1 [29]. Agents that increase cyclic GMP can also activate KATP channels in vascular smooth muscle (reviewed in Ref. [20]) and cardiomyocytes [30], which can involve cyclic GMP-dependent kinase [30] or Ras and mitogen-activated protein kinase kinase [31]. However, their contribution to NO-meditated vasodilatation is minimal under physiological conditions [20,21,23,25,32]. By contrast, vasoconstrictors (Fig. 2) such as vasopressin endothelin and angiotensin II inhibit KATP currents in isolated myocytes via protein kinase C activation and increased ATP synthesis [13,20,33–35].


Figure 2
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  		Fig. 2 Hormonal regulation of vascular KATP channels. Vasoconstrictors binding to G-protein-coupled receptors activate phospholipase Cβ (PLCβ) which causes protein kinase C (PKC) to phosphorylate the channel. This closes KATP channels and the ensuing depolarization opens voltage-gated calcium channels (VGCC). Vasodilatory receptors that couple to adenylyl cyclase via Gs increase cAMP and activate the KATP channel though PKA-dependent phosphorylation. Nitric oxide, peroxynitrite (ONOO–), reactive oxygen species (ROS) and cGMP combine to activate the KATP channel in sepsis.

 
2.6. Role in pathophysiology
KATP channels are strongly implicated in mediating systemic vasodilatation during tissue hypoxia [21], increasing blood flow to heart, brain and muscle [13,20]. The mechanism of channel activation involves hypoxia-induced release of vasodilators such as NO or adenosine, as well as a direct effect of hypoxia, either via an oxygen sensor and/or changes in cell metabolism [13,20]. Excessive opening will significantly increase plasma K+, as seen during strenuous exercise. Indeed, we have described a ‘K+ channel syndrome’ where pharmacological opening of the channel in the presence of critical illness gave rise to life-threatening hyperkalaemia, which was successfully treated with glibenclamide [16].

KATP channels within the brain and heart are also strongly implemented in the phenomenon of ischaemic preconditioning, whereby sublethal ischaemia protects against a subsequent and otherwise lethal insult (reviewed in Refs. [12,13,36]). Such a role is reinforced by the observation that message and protein levels for Kir6.1 markedly increase during prolonged myocardial ischaemia [37] or post-hypoxia [38]. A similar protective effect can also be achieved with low-dose endotoxin (lipopolysaccharide) [39,40]. Protection is thought to be afforded, at least in part, by action potential shortening and/or a decreased firing rate, resulting in reduced Ca2+ overload and a lower energy demand [12,36].


   3. KATP channels and sepsis
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 Abstract
 1. Pathophysiology of septic...
 2. KATP channel structure...
 3. KATP channels and...
4. What influences KATP...
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3.1. In vivo studies
In vivo evidence for KATP channel involvement in sepsis comes mainly from anaesthetised, endotoxic rat [23,41], dog [21] and pig [22,42] models. Immediate restoration of blood pressure can be achieved with glibenclamide, resulting largely from an increase in systemic vascular resistance rather than an effect on cardiac output [21,42]. Glibenclamide also increased vasopressor responses to {alpha}1-adreneoceptor agonists following either short (3 h) [41] or long-term (24 h) [23] exposure to endotoxin. Since glibenclamide had no effect in control animals, this strongly suggests that KATP channels preferentially open during sepsis and are an important underlying cause of hypotension and vascular hyopreactivity. This might also explain the increased responsiveness to pharmacological channel activators following endotoxin treatment [23,43]. Significantly, potentiation of KATP channel function, vascular hyporeactivity and the pressor effect of glibenclamide could be prevented by pre-treatment with the corticosteroid, dexamethasone [43]. This may be related to dexamethasone either inhibiting channel subunit expression and/or synthesis of a mediator regulating expression. Indeed, both mRNA and protein levels for Kir6.1 were substantially increased in the diaphragm of endotoxin-treated rats, with levels peaking over 24–48 h [44]. Similarly, Kir6.1 gene expression was up-regulated 22-fold in experimental colitis [45]. Thus increased KATP channel expression is a common feature of metabolic stress, though whether this is beneficial or detrimental in sepsis remains to be determined. Based on animal studies one could hypothesise that a reduction in channel expression may underlie the clinical benefit of glucocorticoid agents demonstrated in septic patients [46].

The involvement of KATP channels in the vascular disturbances associated with sepsis was questioned in a recent placebo-controlled study in septic shock patients where glibenclamide had no effect on blood pressure or norepinephrine requirements [47]. Although at first sight, this would appear at odds with the animal literature, it probably reflects the failure of SUR inhibitors at standard therapeutic doses to adequately block the vascular channel, particularly when opened during metabolic stress (see later).

3.2. Organ bath studies
Vascular hyporeactivity can also be demonstrated using in vitro organ bath models [6,23,32,41,48]. Here, arterial rings (± an intact endothelium) are taken from blood vessels of either septic/endotoxic animals (ex-vivo) or from healthy animals which are incubated with endotoxin (in vitro). Decreased contractility is readily shown as a flatter dose-response curve to catecholamine vasoconstrictors, where both potency and maximal tension are decreased (e.g. [48]). The maintained ability of endotoxin to induce in vitro vascular hyporeactivity in vessels without endothelium is not surprising given that iNOS is expressed in all layers within the blood vessel under these conditions [49,50].

Abnormal opening of KATP channels and, to a lesser extent, large conductance Ca2+-activated K+ (BKCa) channels, is responsible for the increase in membrane hyperpolarization reported in mesenteric artery and aorta taken from rats exposed to endotoxin for up to 6 h [51–53]. At the same timepoint, drugs that close KATP channels via pore inhibition (PNU-37883A and barium) [24,54] almost fully restored tension to the {alpha}1-adrenoceptor agonist, phenylephrine [25]. Less reversal was achieved at 20 h, suggesting additional mechanisms underlying hyporeactivity and/or irreversible damage to the contractile machinery. Likewise, relaxations to KCOs are potentiated in both in vitro and ex-vivo models of endotoxin-induced hyporeactivity [23,32,51], indicative of up-regulation of KATP channel function in vascular smooth muscle.

A somewhat surprising but consistent finding in in vitro models is the lack of effect of SUR inhibitors on vascular hyporeactivity and in some cases, contractions were even further reduced [23,25,41,55]. An intriguing possibility is that endotoxin alters KATP channel pharmacology such that channel inhibition via the SUR becomes dysfunctional. We previously found that SUR inhibitors become significantly less effective at inhibiting levcromakalim-or iNOS-induced vascular relaxation in the presence of endotoxin [32]. In contrast, the vascular selective pore inhibitor, PNU-37883A remained effective. Perhaps less intuitive is why glibenclamide is efficacious in in vivo animal studies. This may relate to the much higher dosages used (10 to 100-fold compared to in vitro studies), at which concentration glibenclamide may be also acting on the pore-forming subunit [11]. Moreover, these in vivo doses (10–40 mg/kg) are far in excess of those given to humans (upper limit ~0.25 mg/kg) but within the dose-range necessary to block the hypotensive effects of pinacidil in rats [24]. Thus, the dose of glibenclamide required to effectively block vascular KATP channels would probably never be given to patients.


   4. What influences KATP channel activation and function in sepsis?
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 1. Pathophysiology of septic...
 2. KATP channel structure...
 3. KATP channels and...
 4. What influences KATP...
References
 
4.1. Nitric oxide/cyclic GMP pathway
Endotoxin-induced hypotension and vascular hyporeactivity are largely a consequence of over-production of iNOS-derived NO within the blood vessel wall [5,49]. Increased production of NO, albeit at much lower levels, is found in septic patients [5,49] and is reported to be inversely correlated with mean arterial pressure and systemic vascular resistance [56]. Compared to animals, induction of iNOS appears restricted in humans, occurring mainly in blood vessels at the very point of infection [56] or in neutrophils [57]. Taken together, this suggests NO derived from iNOS may not be the only source of NO in human sepsis [49]. However, a marked pressor response was still achieved in septic shock patients receiving a non-specific NOS inhibitor [8], suggestive of increased sensitivity to NO in humans. Once formed, NO can activate soluble guanylate cyclase and increase cyclic GMP, or can react with superoxide to form peroxynitrite, a process that occurs more readily during systemic inflammation [4]. Peroxynitrite is more reactive than NO, capable of nitrating tyrosine residues and reacting with thiols and iron-containing proteins, sometimes irreversibly.

In the short term (<6 h), the NO/cyclic GMP pathway is likely to account for KATP channel activation. This is based on the observation that NOS or guanylate cyclase inhibitors fully reversed endotoxin-induced hyporeactivity or membrane hyperpolarisation, and that KATP channel blockers had effects of near-similar magnitude [25,32,48,53]. An early indication that NO may activate KATP channels in sepsis was the finding that extracellular L-arginine, which is required for continued cellular NO production by iNOS, caused persistent activation of KATP channels in endotoxin-treated (24 h) but not control vascular smooth muscle cells [58]. Interestingly, persistent channel activation could not be mimicked by exogenous NO, strongly suggesting that the iNOS pathway yields additional or more stable factors that work in concert with NO. Likewise, the involvement of KATP channels in NO-mediated relaxation requires prior endotoxin treatment [32] or the formation of peroxynitrite, which itself produces glibenclamide-sensitive relaxation in blood vessels [59,60]. In addition, prolonged NO and/or superoxide generation will inhibit calcineurin activity [61], the net effect might be to hyperphosphorylate the KATP channel and cause substantial opening, even at normal ATP levels [14].

4.2. Calcitonin gene related peptide
This 37 amino acid peptide contained within sensory nerve endings acts as a neurotransmitter in vasodilator nerves scattered throughout most arterial beds. CGRP has been implicated in the pathophysiology of septic shock with plasma levels substantially rising in human and animal forms of shock, which correlated with disease severity [62,63]. In addition, administration of a receptor antagonist (hCGRP) transiently reversed tachycardia and hypotension in endotoxin-treated rats [64]. As mentioned previously, CGRP activates vascular KATP channels through PKA-mediated phosphorylation [13,20]. This has physiological relevance since glibenclamide partially reverses relaxation of a variety of blood vessels exposed to CGRP both in vivo and in vitro [20,28]. There may also be contributions from other neurohormal activators of KATP channels, including atrial natriuretic peptide and adenosine [20], which also rise in septic patients [65,66].

4.3. The actin cytoskeleton: more than scaffolding for KATP channels?
The actin cytoskeleton consists of the protein actin, which exists as polymerised (F) or unpolymerized globular (G) actin and together represents ~50% of total protein content within the cell [67]. Both F and G actin are in a dynamic, energy-dependent flux and have been implicated in the control of contractility, cell motility and various ion channels [67,68], including the KATP channel. In vascular muscle, actin cytoskeletal organization via the GTPase, RhoA constitutes a major pathway for sustaining contractions [68,69]. Since cyclic GMP inhibits RhoA, this pathway could become downregulated in prolonged sepsis and contribute to irreversible hypocontractility.

Actin depolymerisation is known to increase KATP channel opening in isolated cardiac myocytes and attenuate the inhibitory action of sulphonylureas [70,71]. It also abolishes high-affinity glibenclamide binding to the SUR in vascular smooth muscle [72,73]. Likewise, metabolic stress reduces SUR binding, probably through Mg2+ ADP [13]. This pattern is remarkably similar to that seen with the SUR inhibitor, glibenclamide in both in vitro [25,32] and in vivo [74] sepsis, but not with the specific pore blocker, PNU-37883A. Such a mechanism may help to explain the differences observed between KATP channel inhibitors having different sites of action (SUR versus pore) (Fig. 3). Cytoskeletal disruption in sepsis may occur through a decrease in energy status (see later), as normal assembly and maintenance of the actin cytoskeleton is reliant upon polymerization, an ATP-dependent process [67]. NO, which inhibits mitochondrial respiration, disrupts the actin cytoskeleton in various cell types, including kidney, liver and lamina propia of the small intestine [75–77], through either nitration [75,77], nitrosylation [78] or inhibition of RhoA kinase[69]. The actin cytoskeleton is also disrupted in bovine aortic and pulmonary vascular endothelial cells following endotoxin or TNF{alpha} treatment [79,80], though whether this occurs in smooth muscle remains unknown.


Figure 3
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  		Fig. 3 Schematic of altered KATP channel properties in sepsis The KATP channel consists an ion-channel pore and a sulphonylurea receptor subunit (SUR), interacting at their N and C termini, respectively [12]. Under physiological conditions KATP channel openings are infrequent. In sepsis these markedly increase in part due to a fall in the ATP/ADP ratio, and/or cytoskeletal disruption. This is proposed to cause a conformational change of the channel, accounting for reduced binding and efficacy of SUR inhibitors, with little effect on PNU-37883A (PNU) interaction. NBF; nucleotide binding fold. Glib:glibenclamide.

 
4.4. Changes in energy status
KATP channels may be opened by a fall in [ATP]i, pH or oxygen tension, or by a rise in intracellular lactate and NDPs [6,7]. These may facilitate NO activation of the channel or act independently. Many of these factors operate in sepsis though the extent to which these play a role will depend on the degree of perturbation of the individual variable as well as severity and duration of the septic insult. Lactic acidosis is consistently reported in animal and human sepsis (e.g. [21,81]) and probably results from increased activity of skeletal muscle Na+K+– ATPase rather than tissue hypoxia [81]. Likewise, raised tissue oxygen tensions are reported, for example, in skeletal muscle [82] and bladder epithelium [83] during sepsis. This finding, in conjunction with decreased global oxygen consumption, suggests adequate availability but decreased cellular utilisation of oxygen, giving rise to a state of ‘cytopathic dysoxia’ related to mitochondrial dysfunction, increased generation of NO and decreased ATP production [4,84]. The ensuing ‘energy failure’ is implicated in the pathophysiology of organ failure. Of note, ATP levels are preserved in the skeletal muscle of eventual survivors of septic shock but fall in non-surviving patients [85]. This fall in ATP has been replicated in other tissues in various animal models [86,87]. Thus, opening of KATP channels due to metabolic failure may only be significant in severe sepsis although, in vascular smooth muscle, this is likely to depend to a greater extent on the change in NDP levels because of the main subtype (SUR2B/Kir6.1) expressed in this tissue [13].

4.5. The mitoKATP channel and organ dysfunction
In patients and animal models of sepsis, mitochondria are swollen and distorted, with disruption of the matrix [88–90]. These changes are associated with a decrease in cellular oxidative capacity [90]. Matrix volume is considered an important regulator of mitochondrial metabolism [91]. Under physiological conditions, continual K+ influx across the inner membrane is accompanied by the passage of anions and water. To maintain mitochondrial integrity, movement of K+ out of the matrix is achieved through the K+/H+ exchanger. MitoKATP channels are thought to contribute to this mitochondrial K+ influx (reviewed in Refs. [36,92]). Observations that KCOs increase matrix volume in a K+-dependent fashion, while glibenclamide and ATP inhibit swelling, support this view [92,93]. Increases in matrix volume can protect against ischaemic damage by preserving structure and function of the intermembrane space and the low permeability of the outer membrane to ADP and ATP [91]. However excessive, uncompensated mitoKATP opening may cause significant depolarisation with rupture of the outer membrane, opening of the mitochondrial permeability transition pore, loss of cytochrome C [91,93] and triggering of cell death pathways. However, a lesser degree of membrane depolarisation may afford protection from cell damage and death by reducing ROS production, thereby preventing mitochondrial Ca2+ overload and opening of the transition pore [92].

Evidence suggests that mitoKATP channels may offer protection against apoptosis [92,94], possibly by acting as an upstream antagonist of p53 [95]. This could explain why apoptosis is not a widespread phenomenon in sepsis and appears limited to gut epithelia, lymphocytes, splenocytes and neurones in the cardiovascular autonomic centres [2,96]. The extent to which these mitoKATP channel-related mechanisms operate in sepsis is unknown. Progress is hindered by the unknown molecular identity of these channels as well as the likely contribution from plasma KATP channels to cellular protection [36].

4.6. Glucose homeostasis and insulin
During sepsis, disordered cell metabolism undoubtedly contributes to the development of MOF. Hyperglycaemia associated with insulin resistance is a common feature [2]. Tight control of glucose levels with additional infusion of insulin and glucose reduces mortality and morbidity in critically ill surgical [97] and medical ICU patients [98]. Regulation of blood sugar has been proposed to involve a reciprocal interaction between pancreatic beta cells and the ventromedial hypothalamus, with KATP channel activity controlling both insulin and glucagon secretion [19]. Thus, a consequence of excessive channel activation would result in high circulating levels of glucagon, decreased insulin release, and reduced glucose uptake in skeletal muscle, all of which will contribute to insulin resistance in sepsis.

Persistent hyperglycaemia has a number of toxic effects, promoting inflammation, oxidative stress and apoptosis [99]. In the context of ischaemic heart failure, many of these processes can be reversed by insulin treatment [99]. This is independent of blood glucose concentration but involves actin cytoskeleton-dependent activation of KATP channels [100,101]. Improved outcomes in critical illness with ‘tight glycaemic control’ appear due to a combination of prevention of direct glucose toxicity and insulin-independent effects on glucose control [102]. Of note, intensive insulin therapy in critically ill patients preserved hepatic mitochondrial ultrastructure and respiratory function [90].

4.7. K+ channels as key regulators of immune function
Circulating neutrophils play a pivotal role in the killing of a range of pathogens. In human neutrophils, activation of the BKCa channel is an absolute requirement for microbial killing, which functions to provide a potassium-rich environment necessary for activation of proteases within the phagocytic vacuole [103]. In macrophages, endotoxin-induced cytokine release [104–106] and NO production [41,107] needs prior activation of a number of K+ channels, including BKCa, Kv and KATP channels. This released NO has an important cytotoxic function in the killing of micro-organisms. Thus K+ channels appear to play an essential role in the early activation of immune cells.

4.8. Clinical implications and summary
Sepsis still carries a high mortality rate and a comprehensive understanding of the underlying pathophysiology remains elusive. The significance of many mechanisms elucidated in laboratory models remains to be confirmed in patients. Animal studies are usually reductionist in nature, employ very aggressive insults and are of short duration. They may not be representative of a long-term, fluid-resuscitated, anaesthetised patient, often presenting with co-morbidities, who is receiving multiple pharmacological and mechanical organ support.

The above caveats certainly apply to the KATP channel. Excessive activation of the KATP channel is clearly implicated in a number of crucial mechanisms in sepsis, including vascular hyporeactivity and insulin resistance. However, channel opening may afford a degree of cellular protection. Arguably, the balance between good and detrimental effects will depend critically on concurrent energy status, as low ATP and high NDP levels will induce greater channel opening, with the consequences of decreased insulin release and subsequent hyperglycaemia, disruption of the mitochondrial matrix with a further reduction in energy production, leading to profound, if not irreversible, vascular hyporesponsiveness (Fig. 4).


Figure 4
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  		Fig. 4 Cartoon illustrating potential mechanisms by which endotoxin opens sarcolemmal or mitoKATP channels. Depending on the severity of sepsis, channel opening can lead to cellular protection or organ failure.

 
Therapeutic intervention with channel inhibitors still remains an attractive option, though targeting of the vasculature with specific pore rather than SUR inhibitors would appear more appropriate in sepsis. Clearly further research is needed to better delineate the protective and harmful roles of the KATP channel in sepsis. This may lead to development of tissue-specific, targeted modulators of channel function, which may benefit not only the septic patient, but also other pathological states.


   Acknowledgements
 
Our research is funded by the MRC, British Heart Foundation and Wellcome Trust.


   Notes
 
Time for primary review 15 days


   References
Top
 Abstract
 1. Pathophysiology of septic...
 2. KATP channel structure...
 3. KATP channels and...
 4. What influences KATP...
 References
 

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