<?xml:namespace prefix = o ns = "urn:schemas-microsoft-com:office:office" />

Ma，Penglin MD；Danner，Robert L. MD

Critical Care Medicine Department   National Institutes of Health

Bethesda，MD

Address requests for reprints to：Robert L. Danner，MD，National Institutes of Health，CCM Department，Building 10，Room 7D43，10 Center Drive，MSC 1662，Bethesda，MD 20892－1662.

　　Sepsis，severe sepsis，and septic shock represent hierarchical stages of the systemic response to infection ^[1]. With each escalating level of severity comes a higher toll in organ damage，life－support requirements，and mortality rates. The pinnacle of this deadly triad，septic shock，marks the point when cascading responses to infection overwhelm basic compensatory mechanisms，causing the patient to slip into overt cardiovascular failure. The appearance of vasopressor－requiring hypotension in an infected patient substantially increases the risk of death ^[2，3]. Up to 75％ of septic shock nonsurvivors die in refractory shock during the first 7－10 days of illness ^[4]. Therefore，investigation into the prevention，treatment，and pathophysiology of cardiovascular failure per se is an attractive and vital pillar of septic shock research.

　　Although sepsis－induced hypotension typically manifests itself as a vasodilatory，distributive shock，the underlying hemodynamic derangements are more complex （Fig. 1）. Net vascular tone is determined by the sum of regional balances between relaxation and constriction across physiologically distinct vascular beds ^[5]. A large number of endogenous vasodilators and vasoconstrictors are known to be elevated in septic shock （Table 1）. Many of these vasoactive substances also function as regulators of inflammation and coagulation，and some have been implicated in endothelial injury. Complicating this milieu of mediators，and possibly hampering the development of new treatments，is the important observation that these vasoregulatory pathways are intricately linked ^[6，7]. Intervention in one pathway has ripple effects throughout the interconnected network，often producing unexpected compensatory adjustments that tend to maintain the shock state ^[7]. Furthermore，in refractory septic shock，both vascular relaxation and constriction ultimately become impaired ^[5，8]，an abnormality analogous to endothelial dysfunction in chronic arteriosclerosis ^[9～11].

<?xml:namespace prefix = o ns = "urn:schemas-microsoft-com:office:office" /> 

　　In this issue of Critical Care Medicine，Dr. Takakura and colleagues ^[12] report that peroxynitrite （ONOO－），a strong oxidant produced by the reaction of nitric oxide （NO） with superoxide （O₂ －），inactivates a1－adrenoceptors and thereby may contribute to hypotension and catecholamine hyporeactivity in septic shock. Their investigation was largely conducted in a heterologous in vitro system by using Chinese hamster ovary （CHO） cells transfected with human a1a－，a1b－，and a1d－adrenoceptors. Exogenous ONOO－ decreased the binding capacity of a1a－ and a1d－ but not a1b－ adrenoceptors. Binding affinity was not altered. However，the changes in binding capacity were associated with reductions of norepinephrine－stimulated intracellular calcium release （[Ca₂⁺]i）. Vascular hyporeactivity to pharmacologic doses of catecholamines has been clinically recognized in septic shock for decades，but basic mechanisms underlying the phenomenon have only recently come to light. Research in the late 1980s and early 1990s found that NO，a recently discovered endogenous vasodilator，was an important cause of sepsis－induced shock ^[13，14]. Soon after，NO was linked more specifically to the problem of vascular hyporeactivity. Inhibitors of NO－synthase were found to at least partially restore the vasoconstrictive properties of norepinephrine ^[15，16] and vasopressin ^[17].

　　NO－induced vasodilation occurs primarily through the activation of soluble guanylate cyclase ^[18]. Activation of large conductance Ca₂⁺－activated K⁺ channels by phosphorylation via cyclic guanosine 3，5－monophosphate－dependent protein kinase and，to a lesser degree，by direct nitrosylation causes vessel relaxation ^[19]. The resulting persistent membrane hyperpolarization appears to account for much of the observed vascular hyporeactivity of septic shock ^[18～20]. However，it also has become clear that this NO pathway alone fails to fully explain the vascular failure and hyporeactivity of septic shock ^[20，21]. Notably，NO synthase inhibitors only partially restore vasopressor responsiveness to the septic vasculature. Furthermore，hypotension and death can still be produced in endotoxin－challenged animals lacking inducible NO synthase，the isoform most closely associated with septic shock ^[22].

　　The mechanism of vascular hyporeactivity investigated by Dr. Takakura and colleagues ^[12]，sepsis－induced loss of a1－adrenoceptor number，was first recognized in rodent models before the discovery of NO，but its underlying causes were unknown ^[23]. More recently，ONOO－ wasshown to attenuate both a－ and b－adrenoceptor agonist－induced responses in rats ^[24]，thus linking adrenergic receptor dysfunction directly with ONOO－. The incremental advance provided by Dr. Takakura and colleagues ^[12] was to directly demonstrate that ONOO－ could reduce human 1－adrenoceptor binding capacity and function ^[12]. Notably，ONOO－－damaged receptors were less responsive to norepinephrine. Furthermore，these mechanistic studies conducted in a transfected cell line were shown to be consistent with the effects of ONOO－ on isolated rat aortas.

<?xml:namespace prefix = o ns = "urn:schemas-microsoft-com:office:office" /> 

32. Szabo C，Cuzzocrea S，Zingarelli B，et al： Endothelial dysfunction in a rat model of endotoxic shock. Importance of the activation of poly （ADP－ribose） synthetase by peroxynitrite. J Clin Invest 1997；100：723－735 [Context Link]

33. Chabot F，Mitchell JA，Quinlan GJ，et al：Characterization of the vasodilator properties of peroxynitrite on rat pulmonary artery： Role of poly （adenosine 5 －diphosphoribose） synthase. Br J Pharmacol 1997；121：485－490 [Context Link]

34. Freeman BD，Danner RL，Banks SM，et al：Safeguarding patients in clinical trials with high mortality rates. Am J Respir Crit Care Med 2001；164：190－192 [Context Link]

35. NIH－sponsored conference on the functional genomics of critical illness and injury. NIH Web site. Available at： http：//www.cc.nih.gov/ccmd/ Symposium2002/index.html Accessed Feb. 8，2002 [Context Link]

36. Consortium for expression profile studies in sepsis （CEPSIS）. Web site. Available at：http：//www.CIA.wustl.edu/CEPSIS.html Accessed Feb. 8，2002 [Context Link]