Nitric oxide in shock
2007; Elsevier BV; Volume: 72; Issue: 5 Linguagem: Inglês
10.1038/sj.ki.5002340
ISSN1523-1755
Autores Tópico(s)Renal function and acid-base balance
ResumoRefractory hypotension with end-organ hypoperfusion and failure is an ominous feature of shock. Distributive shock is caused by severe infections (septic shock) or severe systemic allergic reactions (anaphylactic shock). In 1986, it was concluded that nitric oxide (NO) is the endothelium-derived relaxing factor that had been discovered 6 years earlier. Since then, NO has been shown to be important for the physiological and pathological control of vascular tone. Nevertheless, although inhibition of NO synthesis restores blood pressure, NO synthase (NOS) inhibition cannot improve outcome, on the contrary. This implies that NO acts as a double-edged sword during septic shock. Consequently, the focus has shifted towards selective inducible NOS (iNOS) inhibitors. The contribution of NO to anaphylactic shock seems to be more straightforward, as NOS inhibition abrogates shock in conscious mice. Surprisingly, however, this shock-inducing NO is not produced by the inducible iNOS, but by the so-called constitutive enzyme endothelial NOS. This review summarizes the contribution of NO to septic and anaphylactic shock. Although NOS inhibition may be promising for the treatment of anaphylactic shock, the failure of a phase III trial indicates that other approaches are required for the successful treatment of septic shock. Amongst these, high hopes are set for selective iNOS inhibitors. But it might also be necessary to shift gears and focus on downstream cardiovascular targets of NO or on other vasodilating phenomena. Refractory hypotension with end-organ hypoperfusion and failure is an ominous feature of shock. Distributive shock is caused by severe infections (septic shock) or severe systemic allergic reactions (anaphylactic shock). In 1986, it was concluded that nitric oxide (NO) is the endothelium-derived relaxing factor that had been discovered 6 years earlier. Since then, NO has been shown to be important for the physiological and pathological control of vascular tone. Nevertheless, although inhibition of NO synthesis restores blood pressure, NO synthase (NOS) inhibition cannot improve outcome, on the contrary. This implies that NO acts as a double-edged sword during septic shock. Consequently, the focus has shifted towards selective inducible NOS (iNOS) inhibitors. The contribution of NO to anaphylactic shock seems to be more straightforward, as NOS inhibition abrogates shock in conscious mice. Surprisingly, however, this shock-inducing NO is not produced by the inducible iNOS, but by the so-called constitutive enzyme endothelial NOS. This review summarizes the contribution of NO to septic and anaphylactic shock. Although NOS inhibition may be promising for the treatment of anaphylactic shock, the failure of a phase III trial indicates that other approaches are required for the successful treatment of septic shock. Amongst these, high hopes are set for selective iNOS inhibitors. But it might also be necessary to shift gears and focus on downstream cardiovascular targets of NO or on other vasodilating phenomena. Shock may be defined as the failure of the circulation to provide sufficient blood and oxygen to peripheral organs. Key symptoms of shock are severe hypotension and vasoplegia, ultimately resulting in the dysfunction of one or more vital organs, such as kidney, liver, gut, lung, and brain. Life-threatening shock may be caused by acute myocardial infarction (cardiogenic shock), severe fluid or blood loss (hypovolemic or hemorrhagic shock), severe infection (septic shock), or severe allergic reaction (anaphylactic shock). The most common type of shock is hemorrhagic shock; in children, elderly, and immunocompromized people, septic shock is the most common. In the first week after diagnosis, refractory hypotension is the leading cause of death; later on, death is generally caused by multiple organ failure as a result of prolonged hypotension and cytotoxicity. The history of clinical trials in septic patients extends back to 1963, when high-dose hydrocortisone was used.1.Riedemann N.C. Guo R.F. Ward P.A. Novel strategies for the treatment of sepsis.Nat Med. 2003; 9: 517-524Crossref PubMed Scopus (548) Google Scholar But despite almost half a century of clinical trials, and more than two decades of extensive research, only two experimental approaches have survived the numerous clinical trials and have reached the septic patient: low-dose corticosteroids and recombinant human activated protein C.1.Riedemann N.C. Guo R.F. Ward P.A. Novel strategies for the treatment of sepsis.Nat Med. 2003; 9: 517-524Crossref PubMed Scopus (548) Google Scholar,2.Deans K.J. Haley M. Natanson C. et al.Novel therapies for sepsis: a review.J Trauma. 2005; 58: 867-874Crossref PubMed Scopus (79) Google Scholar Still, their beneficial effect on survival seems to depend on the severity of the illness and they may be rather harmful in patients with a lower risk of death.2.Deans K.J. Haley M. Natanson C. et al.Novel therapies for sepsis: a review.J Trauma. 2005; 58: 867-874Crossref PubMed Scopus (79) Google Scholar In addition, recent trials failed to show any significant benefit of recombinant human activated protein C and indicated an increased risk of bleeding, making it unclear whether its alleged beneficial effects in fact outweigh its risks.3.Eichacker P.Q. Natanson C. Increasing evidence that the risks of rhAPC may outweigh its benefits.Intensive Care Med. 2007; 33: 396-399Crossref PubMed Scopus (52) Google Scholar Thus, severe sepsis and septic shock are still associated with an unacceptably high mortality rate of 50–70%. Short-term mortality from septic shock has decreased in recent years. In one study, for example, mortality fell from 62% in the early 1990s to 56% in 2000.4.Annane D. Bellissant E. Cavaillon J.M. Septic shock.Lancet. 2005; 365: 63-78Abstract Full Text Full Text PDF PubMed Scopus (793) Google Scholar Nevertheless, overall mortality is increasing, as the incidence of sepsis is growing by 9% each year.4.Annane D. Bellissant E. Cavaillon J.M. Septic shock.Lancet. 2005; 365: 63-78Abstract Full Text Full Text PDF PubMed Scopus (793) Google Scholar,5.Martin G.S. Mannino D.M. Eaton S. et al.The epidemiology of sepsis in the United States from 1979 through 2000.N Engl J Med. 2003; 348: 1546-1554Crossref PubMed Scopus (3168) Google Scholar Consequently, these days more people die annually from septic shock than from myocardial infarction, lung or breast cancer, stroke, or trauma.6.Nguyen H.B. Rivers E.P. Abrahamian F.M. et al.Severe sepsis and septic shock: review of the literature and emergency department management guidelines.Ann Emerg Med. 2006; 48: 28-54Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar Anaphylaxis can occur in response to any allergen, most commonly insect stings, food, and drugs such as antibiotics, contrast materials, and anesthetics. In general, about 1% of people with an allergic history are prone to anaphylaxis, but some authors consider up to 15% of the US population ‘at risk’.7.Neugut A.I. Ghatak A.T. Miller R.L. Anaphylaxis in the United States: an investigation into its epidemiology.Arch Intern Med. 2001; 161: 15-21Crossref PubMed Google Scholar Overall, the frequency of anaphylaxis is increasing because of the soaring incidence of allergies and the increased number of potential allergens to which people are exposed. In 1980, Furchgott and Zawadzki8.Furchgott R.F. Zawadzki J.V. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine.Nature. 1980; 288: 373-376Crossref PubMed Scopus (0) Google Scholar reported that endothelial cells release a labile factor that causes blood vessel relaxation. In 1986, it was suggested, and subsequently confirmed, that this endothelial-derived relaxing factor is the short-lived, gaseous, highly reactive radical nitric oxide (NO).9.Furchgott R. Studies on relaxation of rabbit aorta by sodium nitrite: the basis for the proposal that the acid-activatable inhibitory factor from retractor penis is inorganic nitrate the endothelium-derived relaxing factor is nitric oxide.in: Vanhoutte P.M. Vasodilatation: Vascular Smooth Muscle, Peptides, Autonomic Nerves, and Endothelium. Raven Press, New York1988: 401-414Google Scholar, 10.Ignarro L.J. Burns R. Wood K. Biochemical pharmacological properties of EDRF its similarity to nitric oxide.in: Vanhoutte P.M. Vasodilatation: Vascular Smooth Muscle, Peptides, Autonomic Nerves, and Endothelium. Raven Press, New York1988: 427-435Google Scholar, 11.Palmer R.M. Ferrige A.G. Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor.Nature. 1987; 327: 524-526Crossref PubMed Google Scholar, 12.Ignarro L.J. Buga G.M. Wood K.S. et al.Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide.Proc Natl Acad Sci USA. 1987; 84: 9265-9269Crossref PubMed Google Scholar, 13.Ignarro L.J. Byrns R.E. Buga G.M. et al.Endothelium-derived relaxing factor from pulmonary artery and vein possesses pharmacologic and chemical properties identical to those of nitric oxide radical.Circ Res. 1987; 61: 866-879Crossref PubMed Google Scholar NO is produced enzymatically by three different NO synthases (NOS). Neuronal NOS (nNOS) (NOS1) and endothelial NOS (eNOS) (NOS3) are constitutive enzymes important for homeostatic processes, such as neurotransmission and vascular tone, respectively. They produce small amounts of NO in response to increases in intracellular calcium. More recently, the constitutive nature of eNOS has achieved new dimensions, as it became clear that the enzyme's activity may be regulated, both transcriptionally and post-transcriptionally, with acylation, phosphorylation, subcellular localization, and protein interactions determining its activity.14.Fleming I. Busse R. Molecular mechanisms involved in the regulation of the endothelial nitric oxide synthase.Am J Physiol Regul Integr Comp Physiol. 2003; 284: R1-R12Crossref PubMed Google Scholar The third enzyme, inducible NOS (iNOS) (NOS2), is normally not expressed, but is synthesized de novo in response to inflammation. It is calcium-independent and produces large amounts of NO over prolonged periods of time.15.Morris Jr, S.M. Billiar T.R. New insights into the regulation of inducible nitric oxide synthesis.Am J Physiol. 1994; 266: E829-E839PubMed Google Scholar NOS enzymes make NO from L-arginine, and thus competitive L-arginine analogues may prevent them from producing NO. These analogues include NG-monomethyl-L-arginine (L-NMMA), NG-nitro-L-arginine (L-NNA), and NG-nitro-L-arginine methyl ester (L-NAME). As early as 1989, some of these compounds were already successfully used to demonstrate the important physiological role of NO in normal blood pressure homeostasis.16.Aisaka K. Gross S.S. Griffith O.W. et al.NG-methylarginine, an inhibitor of endothelium-derived nitric oxide synthesis, is a potent pressor agent in the guinea pig: does nitric oxide regulate blood pressure in vivo?.Biochem Biophys Res Commun. 1989; 160: 881-886Crossref PubMed Google Scholar,17.Rees D.D. Palmer R.M. Moncada S. Role of endothelium-derived nitric oxide in the regulation of blood pressure.Proc Natl Acad Sci USA. 1989; 86: 3375-3378Crossref PubMed Google Scholar Shortly after the discovery that NO is an important endogenous regulator of vascular tone, its fundamental contribution to inflammatory and septic shock became obvious as well. The NO metabolites nitrite and nitrate (collectively labeled NOx−), indicators of NO production, rise progressively in various animal shock models.18.Feihl F. Waeber B. Liaudet L. Is nitric oxide overproduction the target of choice for the management of septic shock?.Pharmacol Ther. 2001; 91: 179-213Crossref PubMed Scopus (113) Google Scholar In small rodents, plasma concentrations of hundreds to even thousands micromolar may be detected. In larger mammals and humans, however, overproduction does not occur to the same extent and levels rarely increase above 100 μM, or more than 50% above background, despite major circulatory failure.18.Feihl F. Waeber B. Liaudet L. Is nitric oxide overproduction the target of choice for the management of septic shock?.Pharmacol Ther. 2001; 91: 179-213Crossref PubMed Scopus (113) Google Scholar Nevertheless, the critical role of NO in shock has been clearly established, as NOS inhibitors prevent, revert, or at least minimize hypotension in shock induced by lipopolysaccharide (LPS), tumor necrosis factor (TNF), interleukin-1, interleukin-2, or hemorrhage.19.Thiemermann C. Vane J. Inhibition of nitric oxide synthesis reduces the hypotension induced by bacterial lipopolysaccharides in the rat in vivo.Eur J Pharmacol. 1990; 182: 591-595Crossref PubMed Scopus (450) Google Scholar, 20.Kilbourn R.G. Jubran A. Gross S.S. et al.Reversal of endotoxin-mediated shock by NG-methyl-L-arginine, an inhibitor of nitric oxide synthesis.Biochem Biophys Res Commun. 1990; 172: 1132-1138Crossref PubMed Scopus (418) Google Scholar, 21.Kilbourn R.G. Gross S.S. Jubran A. et al.NG-methyl-L-arginine inhibits tumor necrosis factor-induced hypotension: implications for the involvement of nitric oxide.Proc Natl Acad Sci USA. 1990; 87: 3629-3632Crossref PubMed Google Scholar, 22.Kilbourn R.G. Gross S.S. Lodato R.F. et al.Inhibition of interleukin-1-alpha-induced nitric oxide synthase in vascular smooth muscle and full reversal of interleukin-1-alpha-induced hypotension by N omega-amino-L-arginine.J Natl Cancer Inst. 1992; 84: 1008-1016Crossref PubMed Google Scholar, 23.Kilbourn R.G. Fonseca G.A. Griffith O.W. et al.NG-methyl-L-arginine, an inhibitor of nitric oxide synthase, reverses interleukin-2-induced hypotension.Crit Care Med. 1995; 23: 1018-1024Crossref PubMed Scopus (54) Google Scholar, 24.Thiemermann C. Szabo C. Mitchell J.A. et al.Vascular hyporeactivity to vasoconstrictor agents and hemodynamic decompensation in hemorrhagic shock is mediated by nitric oxide.Proc Natl Acad Sci USA. 1993; 90: 267-271Crossref PubMed Scopus (254) Google Scholar NOS inhibition also successfully and rapidly elevates blood pressure and systemic vascular resistance in septic shock patients.25.Petros A. Bennett D. Vallance P. Effect of nitric oxide synthase inhibitors on hypotension in patients with septic shock.Lancet. 1991; 338: 1557-1558Abstract PubMed Google Scholar, 26.Petros A. Lamb G. Leone A. et al.Effects of a nitric oxide synthase inhibitor in humans with septic shock.Cardiovasc Res. 1994; 28: 34-39Crossref PubMed Google Scholar, 27.Avontuur J.A. Tutein Nolthenius R.P. van Bodegom J.W. et al.Prolonged inhibition of nitric oxide synthesis in severe septic shock: a clinical study.Crit Care Med. 1998; 26: 660-667Crossref PubMed Scopus (88) Google Scholar, 28.Lopez A. Lorente J.A. Steingrub J. et al.Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: effect on survival in patients with septic shock.Crit Care Med. 2004; 32: 21-30Crossref PubMed Google Scholar The first studies on NOS inhibition immediately triggered great hopes for a new treatment of refractory hypotension in (septic) shock, but even the earliest studies already indicated the potential harm of NOS inhibitors, as they also caused a progressive fall in cardiac output, amplified organ dysfunction, and even increased mortality.26.Petros A. Lamb G. Leone A. et al.Effects of a nitric oxide synthase inhibitor in humans with septic shock.Cardiovasc Res. 1994; 28: 34-39Crossref PubMed Google Scholar, 29.Klabunde R.E. Ritger R.C. NG-monomethyl-L-arginine (NMA) restores arterial blood pressure but reduces cardiac output in a canine model of endotoxic shock.Biochem Biophys Res Commun. 1991; 178: 1135-1140Crossref PubMed Google Scholar, 30.Cobb J.P. Natanson C. Hoffman W.D. et al.N omega-amino-L-arginine, an inhibitor of nitric oxide synthase, raises vascular resistance but increases mortality rates in awake canines challenged with endotoxin.J Exp Med. 1992; 176: 1175-1182Crossref PubMed Google Scholar, 31.Shultz P.J. Raij L. Endogenously synthesized nitric oxide prevents endotoxin-induced glomerular thrombosis.J Clin Invest. 1992; 90: 1718-1725Crossref PubMed Google Scholar, 32.Teale D.M. Atkinson A.M. L-canavanine restores blood pressure in a rat model of endotoxic shock.Eur J Pharmacol. 1994; 271: 87-92Crossref PubMed Scopus (23) Google Scholar, 33.Liaudet L. Rosselet A. Schaller M.D. et al.Nonselective versus selective inhibition of inducible nitric oxide synthase in experimental endotoxic shock.J Infect Dis. 1998; 177: 127-132Crossref PubMed Google Scholar Exacerbated organ damage was first reported for the kidney,31.Shultz P.J. Raij L. Endogenously synthesized nitric oxide prevents endotoxin-induced glomerular thrombosis.J Clin Invest. 1992; 90: 1718-1725Crossref PubMed Google Scholar but later studies revealed increased injury in other organs as well, including liver, lung, pancreas, and intestines.18.Feihl F. Waeber B. Liaudet L. Is nitric oxide overproduction the target of choice for the management of septic shock?.Pharmacol Ther. 2001; 91: 179-213Crossref PubMed Scopus (113) Google Scholar Unfortunately, even a phase III clinical trial had to be prematurely terminated because of increased mortality in the septic patients treated with the NOS inhibitor, despite positive effects on blood pressure and vascular resistance.28.Lopez A. Lorente J.A. Steingrub J. et al.Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: effect on survival in patients with septic shock.Crit Care Med. 2004; 32: 21-30Crossref PubMed Google Scholar Together, these observations clearly indicate that NO not only mediates hypotension in septic shock, but may also perform an important obligatory role in assorted beneficial pathways. Different explanations may be suggested for the dual personality of NO during septic shock. First of all, there is no doubt about the detrimental effect of excessive NO on vasorelaxation, hypotension, and shock. The NO-mediated hypotension leads to severe hypoxia in peripheral vital organs, resulting in progressive organ failure. NO may also directly contribute to tissue and organ injury by its direct, peroxynitrite-mediated cytotoxic effects. It is generally accepted that NO may cause blood vessel relaxation by activating the cyclic guanosine monophosphate (cGMP)-producing enzyme soluble guanylate cyclase (sGC), leading to activation of the cGMP-dependent protein kinases (PKGs). For smooth muscle contraction, calcium-dependent activation of the myosin light chain (MLC) kinase and subsequent phosphorylation of MLC are essential. Several PKG-dependent phosphorylations ultimately converge on the dephosphorylation of MLC and hence relaxation34.Lucas K.A. Pitari G.M. Kazerounian S. et al.Guanylyl cyclases and signaling by cyclic GMP.Pharmacol Rev. 2000; 52: 375-414PubMed Google Scholar (Figure 1). Important molecular targets of PKG include various pumps and channels involved in modulating intracellular calcium levels and membrane potential, leading to decreased cytosolic calcium and relaxation. In addition to changes in intracellular calcium levels and membrane potential, other important targets for PKG in smooth muscle are the pathways regulating the calcium-sensitivity of the contractile machinery, more particularly the regulatory subunit of MLC phosphatase, which may be directly activated by PKG or indirectly via PKG-mediated inactivation of the inhibitory RhoA pathway.35.Schlossmann J. Hofmann F. cGMP-dependent protein kinases in drug discovery.Drug Discov Today. 2005; 10: 627-634Crossref PubMed Scopus (49) Google Scholar,36.Murthy K.S. Signaling for contraction and relaxation in smooth muscle of the gut.Annu Rev Physiol. 2006; 68: 345-374Crossref PubMed Scopus (205) Google Scholar Nevertheless, NO may also contribute independently of sGC and PKG to lower cytosolic calcium levels, for instance via direct S-nitrosation of potassium channels,37.Bolotina V.M. Najibi S. Palacino J.J. et al.Nitric oxide directly activates calcium-dependent potassium channels in vascular smooth muscle.Nature. 1994; 368: 850-853Crossref PubMed Scopus (1282) Google Scholar via NO-dependent peroxynitrite-mediated S-glutathiolation of the sarco/endoplasmic reticulum calcium adenosine triphosphatase (ATPase) (SERCA) pump,38.Adachi T. Weisbrod R.M. Pimentel D.R. et al.S-glutathiolation by peroxynitrite activates SERCA during arterial relaxation by nitric oxide.Nat Med. 2004; 10: 1200-1207Crossref PubMed Scopus (350) Google Scholar or via direct inhibition of cytochrome P450 (CYP). Enzymes of the CYP4A family are known to produce the vasoconstrictor 20-HETE, an inhibitor of BK channels.39.Roman R.J. P-450 metabolites of arachidonic acid in the control of cardiovascular function.Physiol Rev. 2002; 82: 131-185Crossref PubMed Google Scholar Although sGC has long been regarded as the predominant target for NO in the vasculature, the notion and importance of sGC-independent actions has gained considerable interest lately. The sGC-independent pathways would be especially important in certain vascular beds (particularly in the renal and mesenteric vasculature), at high NO concentrations, and/or in the presence of disease,40.Wanstall J.C. Homer K.L. Doggrell S.A. Evidence for, and importance of, cGMP-independent mechanisms with NO and NO donors on blood vessels and platelets.Curr Vasc Pharmacol. 2005; 3: 41-53Crossref PubMed Scopus (0) Google Scholar suggesting that the sGC-independent mechanisms may be important targets for drug development. Second, increased NO may also provide certain benefits to the patient during septic shock. Arterial vasodilation results in arterial underfilling, which is rapidly sensed by the baroreceptors, thereby leading to increased sympathetic outflow and the activation of the renin–angiotensin–aldosterone system. This leads to vasopressin release, renal vasoconstriction and kidney failure, an acute problem in most septic shock patients, which is associated with very high mortality.41.Schrier R.W. Wang W. Acute renal failure and sepsis.N Engl J Med. 2004; 351: 159-169Crossref PubMed Scopus (250) Google Scholar In this context, increased NO release protects the kidney by causing local vasodilation and by inhibiting platelet aggregation and leukocyte adhesion. In addition, NO may also exert protective effects in other organs via its capacity to counteract oxidative stress, shut off apoptosis, prevent platelet aggregation and leukocyte adhesion, induce anti-inflammatory gene expression, and kill pathogens. Originally it was thought that the dual, Janus-faced effects of NO would relate to the NOS isoform responsible for its production, with eNOS providing the essential, protective NO and iNOS causing excessive vasodilation. For a long time, leukocyte iNOS was thus thought to be responsible for the production of shock-inducing NO. The reasons for this assumption are obvious: when iNOS is transcribed, it produces large amounts of NO for a long time.15.Morris Jr, S.M. Billiar T.R. New insights into the regulation of inducible nitric oxide synthesis.Am J Physiol. 1994; 266: E829-E839PubMed Google Scholar In addition, rodent macrophages may be induced to produce large amounts of NO in vitro;42.Stuehr D.J. Marletta M.A. Mammalian nitrate biosynthesis: mouse macrophages produce nitrite and nitrate in response to Escherichia coli lipopolysaccharide.Proc Natl Acad Sci USA. 1985; 82: 7738-7742Crossref PubMed Google Scholar iNOS was originally identified as ‘macrophage’ NOS;43.Stuehr D.J. Cho H.J. Kwon N.S. et al.Purification and characterization of the cytokine-induced macrophage nitric oxide synthase: an FAD- and FMN-containing flavoprotein.Proc Natl Acad Sci USA. 1991; 88: 7773-7777Crossref PubMed Google Scholar and although human macrophages do not seem to be capable of producing much NO in vitro or ex vivo,44.Denis M. Human monocytes/macrophages: NO or no NO?.J Leukoc Biol. 1994; 55: 682-684PubMed Google Scholar,45.Albina J.E. On the expression of nitric oxide synthase by human macrophages. Why no NO?.J Leukoc Biol. 1995; 58: 643-649PubMed Google Scholar neutrophils from septic patients display abnormally high amounts of iNOS mRNA activity.46.Tsukahara Y. Morisaki T. Horita Y. et al.Expression of inducible nitric oxide synthase in circulating neutrophils of the systemic inflammatory response syndrome and septic patients.World J Surg. 1998; 22: 771-777Crossref PubMed Scopus (35) Google Scholar,47.Goode H.F. Howdle P.D. Walker B.E. et al.Nitric oxide synthase activity is increased in patients with sepsis syndrome.Clin Sci (Lond). 1995; 88: 131-133Crossref PubMed Google Scholar More recently, however, it was demonstrated in mice that parenchymal cells, rather than blood cells, are required for the systemic production of NO during septic and endotoxic shock.48.Bultinck J. Sips P. Vakaet L. et al.Systemic NO production during (septic) shock depends on parenchymal and not on hematopoietic cells: in vivo iNOS expression pattern in (septic) shock.FASEB J. 2006; 20: 2363-2365Crossref PubMed Scopus (20) Google Scholar Tissues that do express high levels of iNOS during endotoxemia or bacteremia were identified as liver and intestines.48.Bultinck J. Sips P. Vakaet L. et al.Systemic NO production during (septic) shock depends on parenchymal and not on hematopoietic cells: in vivo iNOS expression pattern in (septic) shock.FASEB J. 2006; 20: 2363-2365Crossref PubMed Scopus (20) Google Scholar,49.Hickey M.J. Sihota E. Amrani A. et al.Inducible nitric oxide synthase (iNOS) in endotoxemia: chimeric mice reveal different cellular sources in various tissues.FASEB J. 2002; 16: 1141-1143PubMed Google Scholar Whether hepatocytes, enterocytes, Paneth cells, or rather vascular cells are the predominant parenchymal source of the enhanced systemic NO, remains to be determined. Studying cell-specific iNOS-deficient or iNOS-reactivation mice may provide the answer to this question. In well-oxygenated conditions, NOS enzymes may produce NO from L-arginine. Some of this NO reaches its targets, such as the smooth muscle cells where it triggers relaxation, but the majority is destroyed by rapid oxidation into nitrite and nitrate. Until recently, these metabolites were considered to be physiologically inert, stable end products, and an index of NO production. However, substantial proof is now emerging that plasma nitrite actually serves as an important vascular storage pool for NO.50.Lundberg J.O. Weitzberg E. NO generation from nitrite and its role in vascular control.Arterioscler Thromb Vasc Biol. 2005; 25: 915-922Crossref PubMed Scopus (198) Google Scholar Previously, it was suggested that S-nitrosated albumin and hemoglobin were the stable transporters of intravascular NO.51.Stamler J.S. Jaraki O. Osborne J. et al.Nitric oxide circulates in mammalian plasma primarily as an S-nitroso adduct of serum albumin.Proc Natl Acad Sci USA. 1992; 89: 7674-7677Crossref PubMed Google Scholar,52.Stamler J.S. Jia L. Eu J.P. et al.Blood flow regulation by S-nitrosohemoglobin in the physiological oxygen gradient.Science. 1997; 276: 2034-2037Crossref PubMed Scopus (790) Google Scholar However, the levels of circulating S-nitrosothiols are either undetectable or in the lower nM range, whereas nitrite is present in concentrations of 0.5–1 μM.50.Lundberg J.O. Weitzberg E. NO generation from nitrite and its role in vascular control.Arterioscler Thromb Vasc Biol. 2005; 25: 915-922Crossref PubMed Scopus (198) Google Scholar,53.Gladwin M.T. Schechter A.N. NO contest: nitrite versus S-nitroso-hemoglobin.Circ Res. 2004; 94: 851-855Crossref PubMed Scopus (55) Google Scholar In addition, nitrite is more stable in blood and it seems that most of it is carried by erythrocytes. The reduction of nitrite back to the vasodilating NO occurs preferentially under hypoxic and/or acidic conditions and may be catalyzed by deoxyhemoglobin, xanthine oxidase, or mitochondrial enzymes50.Lundberg J.O. Weitzberg E. NO generation from nitrite and its role in vascular control.Arterioscler Thromb Vasc Biol. 2005; 25: 915-922Crossref PubMed Scopus (198) Google Scholar (Figure 1). In this way, nitrite derived from either dietary nitrite or nitrate (the latter further reduced by commensal bacteria) or from the oxidation of NOS-produced NO, may have an important function in the endocrine delivery of NO to hypoxic/acidic regions that need vasodilation. The dichotomous effects of NO present one of the biggest challenges to the development of potential therapeutic inhibitors. General inhibition of NOS enzymes improves hemodynamic functions but increases mortality.28.Lopez A. Lorente J.A. Steingrub J. et al.Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: effect on survival in patients with septic shock.Crit Care Med. 2004; 32: 21-30Crossref PubMed Google Scholar, 30.Cobb J.P. Natanson C. Hoffman W.D. et al.N omega-amino-L-arginine, an inhibitor of nitric oxide synthase, raises vascular resistance but increases mortality rates in awake canines challenged with endotoxin.J Exp Med. 1992; 176: 1175-1182Crossref PubMed Google Scholar, 32.Teale D.M. Atkinson A.M. L-canavanine restores blood pressure in a rat model of endotoxic shock.Eur J Pharmacol. 1994; 271: 87-92Crossref PubMed Scopus (23) Google Scholar, 33.Liaudet L. Rosselet A. Schaller M.D. et al.Nonselective versus selective inhibition of inducible nitric oxide synthase in experimental endotoxic shock.J Infect Dis. 1998; 177: 127-132Crossref PubMed Google Scholar Several arguments favor the development of selective iNOS inhibitors to treat septic shock patients.(1)The protective capacity of eNOS-derived NO in septic conditions was underscored by the observation that transgenic overexpression of eNOS partly protected mice fro
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