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Editorial Comment


Fernandes, Daniel; Assreuy, Jamil

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doi: 10.1097/SHK.0b013e3181818518
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NO and sepsis

From the cardiovascular point of view, septic shock is characterized by high cardiac output and decreased peripheral resistance due to dilatation of systemic resistance vessels. The fall in peripheral vascular resistance causes progressive systemic hypotension that is resistant to vasoconstrictors (1). This is associated with a redistribution of cardiac output, with an anomalous organ perfusion/demand ratio that contributes to organ damage and failure (2).

Much of this condition is caused by up-regulation of iNOS (NOS-2) protein expression and the consequent enhanced production of NO (3). Although a staggering amount of mediators are known to be released in sepsis (4), NO has a prominent role in the excessive vasodilatation, vascular hyporeactivity, and vascular leakage (5, 6).

NO and vascular reactivity in sepsis

In the early 1990s, NO emerged as a potentially important player in the pathogenesis of sepsis. A search in the current literature reveals an overwhelming amount of articles dealing with NO in sepsis. However, most reports studying the involvement of NO in septic vascular changes were performed within the first few hours after LPS or bacteria injection, a time when there is a high level of NOS-2 expression (7-9). This line of work made clear that an ongoing NO production is the primary cause of blood pressure drop. As a result, NOS inhibitors injected at these early periods cause an immediate rise in blood pressure and restore vascular reactivity to vasoconstrictors (7, 9). On the other hand, comparatively few reports have studied the mechanisms accountable for the persistence of hypotension and refractoriness to vasoconstrictors after the vanishing of NOS-2 expression/activity. NOS-2 activity is chronologically dissociated from the extensive vasodilatation seen 24 h after LPS infusion in rats, and treatment with N-nitro-l-arginine-methyl ester does not reverse these late vascular effects (10). Rats injected with LPS showed decreased vasoconstriction that could be reversed by NOS inhibitors administered 8 but not 24 h later. Western blots for NOS-2 in the aorta have shown a strong band 8 h but almost no immunoreactive protein 24 h after LPS injection (11). Taken together, these reports suggest that first, the flood of NO derived from NOS-2 activity in the first few hours after LPS in some way modifies the reactivity of the vascular system, and second, that this modification remains for an extended time span. We have previously shown that rats subjected to short-term (30 min) infusion of NO donors (at doses that do not induce detectable increase in plasma NOx levels) exhibited reduced response to phenylephrine and angiotensin II, an effect that was still evident 24 h after this low-dose, short-term infusion of NO donors (12). Recent data from our laboratory have shown an increase in soluble guanylate cyclase (sGC) expression at a late period in time in a sepsis model (cecal ligation and puncture). The rise in sGC amount/activity may help explain, at least in part, the long-lasting NO-induced changes in vascular reactivity in sepsis even with low levels of NOS-2 activity (Fernandes et al., unpublished data).

NO effectors

A variety of molecular targets of NO have been identified and include thiols, metal ions, oxygen and its reactive radicals, heme group, and others (for review, see Ref. [13]). There is still a remarkable controversy concerning the cellular mechanisms responsible for the decrease in vascular smooth muscle reactivity to vasoconstrictors (14). During the last few years, our laboratory has been studying the involvement of sGC and potassium channels as NO effectors especially in sepsis.

Guanylate cyclase

The role of cyclic guanosine monophosphate (cGMP) as an important molecular mechanism of NO-mediated vascular collapse in shock is well recognized. It has been shown that methylene blue, an sGC inhibitor, reestablished the constrictive response to norepinephrine in aorta rings taken from rats injected with LPS (7). A clear association between NO-induced cGMP tissue content and decrease in vascular reactivity, both effects being caused by LPS, was later found (8). These findings were substantiated by in vivo experiments showing that sGC inhibition raised arterial pressure in anesthetized rats (15, 16), rabbits (17), and dogs (18) previously injected with LPS.

The first report studying sGC inhibition in human sepsis was published in 1992 (19), and it showed that methylene blue raised the blood pressure of two patients with septic shock. Several studies soon followed this pioneering work, showing that sGC inhibition by methylene blue resulted in blood pressure increase and reduction in vasopressor requirement (20-28). However, there were reports showing that sGC inhibition would be deleterious to pulmonary vascular tone and cardiac index (20, 25). The issue of efficacy and safety of sGC inhibition in sepsis sparked a debate in the literature that extends to the present day (29-32). We have shown that the highly selective sGC inhibitor ODQ did not succeed in restoring the diminished phenylephrine response in rats injected with LPS 8 h earlier. However, ODQ was effective in restoring phenylephrine efficacy in animals injected with LPS 24 h earlier (11). The failure of sGC inhibitors early after LPS is due to NO-dependent decline in sGC activity/content (33). These results are in line with reports showing that nitroprusside-induced vasodilatation and cGMP accumulation were both inhibited in isolated aorta rings stimulated with interferon γ (34) or LPS (35). These diminished nitroprusside effects depend on NO production by NOS-2 (35, 36). NO produced by NOS-2 decreased sGC mRNA and protein levels in smooth muscle cells stimulated with LPS (37, 38). The diminished sGC amount/activity may be a protective mechanism to limit excessive hypotension and direct NO to microorganism killing. The late recovery in sGC performance depends on de novo enzyme synthesis (33). We have observed that sGC protein/activity levels increase with sepsis progression, and that the enzyme higher performance is related to hypotension and hyporeactivity to vasoconstrictors. Soluble GC up-regulation late in sepsis may be the probable reason why methylene blue is more efficient in improving hypotension and vascular hyporeactivity late in sepsis (Fernandes et al., unpublished data).

To summarize, as a result of NOS-2 activity and NO production early in sepsis, there is a decrease in sGC performance. Together with NOS-2 disappearance and the drop in NO levels, newly synthesized sGC protein provides supranormal enzyme amount and activity. Thus, because sGC performance differs depending on the phase of sepsis, this may be significant for the success or failure of therapy with sGC inhibitors, which may be useful therapeutic strategy if administered at the proper window of opportunity. It should be emphasized that methylene blue was effective in late sepsis, a phase in which other therapeutic approaches are of limited success.

Potassium channels

An important, although less defined, mechanism contributing to the hypotension and the poor response to vasoconstrictors in septic shock involves potassium channels. Potassium channels have a major influence on membrane potential and vascular tone (39, 40) and play an important role in the anomalous vascular tone of sepsis and septic shock. Activation of potassium channels by NO is mediated by cGMP (41-44) or by NO itself (45). The first report linking sepsis and potassium channels has shown that adenosine triphosphate (ATP)-dependent potassium channel blockade improved hypotension in LPS-induced lactic acidosis (46). Rat aorta rings incubated with LPS or obtained from animals injected with LPS displayed the characteristic loss in the response to vasoconstrictors, which was attributed to NO-induced activation of calcium-dependent potassium channels (11, 47, 48). The involvement of NO-activated potassium channels (mainly ATP- and calcium-dependent subtypes) was also noted in the LPS-induced hypotension and hyporeactivity to vasoconstrictors (49) and in the shortening of cardiac action potentials in guinea pigs (50).

As described in the previous section, LPS-induced hyporeactivity to phenylephrine has two distinct phases (10, 11). In the early phase, 8 h after LPS injection, NOS-2-derived NO seems to be directly responsible for vasodilatation and hyporeactivity to vasoconstrictors. In the second phase, 24 h after LPS injection, NOS-2 activity has dropped but vascular hyporeactivity is sustained. Tetraethylammonium (a nonselective potassium channel blocker) reversed the vascular hyporeactivity in both phases (11).

Incubation of NO donors with rat aortic rings induced substantial reduction in phenylephrine-induced contractions. This effect was long-lasting and involved calcium-dependent potassium channels (51). Concurrent to the reduced reactivity to vasoconstrictors, NO donor infusion augmented vascular responses to endothelium-dependent (bradykinin and acetylcholine), but not endothelium-independent (iloprost and single nucleotide polymorphism), vasodilators. Interestingly, this effect was also dependent on potassium channels (12). Therefore, the beneficial effects of potassium channel blockers in reestablishing vascular normality can be credited to two mechanisms, improvement of vasoconstriction and reduction of vasodilatation. Treatment with NO donors also reduced the inflammatory response, and that this effect was potassium channel-dependent (52, 53).

Despite of several reports showing the involvement of ATP-dependent potassium channels in vascular changes in animal models of sepsis (46, 54-56), we (11, 12, 51) and others (57-59) have failed to show the involvement of this channel subtype in vascular changes in sepsis. Recently, two studies expanded these observations to human sepsis. Blockage of ATP-dependent potassium channels failed to rectify the hypotension and to reduce the dose of norepinephrine required to sustain blood pressure (60, 61).

Vascular sensitivity to norepinephrine in healthy volunteers bearing endotoxemia (2 ng/kg LPS, i.v.) was evaluated using the perfused human forearm technique (62). The previously reduced norepinephrine effect was restored by infusion of tetraethylammonium but not of a selective ATP-dependent potassium channel blocker. As we (11, 12, 51) and others (63) have suggested based on experimental studies, vascular calcium-dependent potassium channel subtype seems to be mainly responsible for vascular hyporeactivity during sepsis and may represent a future therapeutic opportunity.

Crucial information on the relationship among all these players during sepsis is still lacking. However, data obtained so far allowed us to compile a timeline of some of the events discussed in this review (Fig. 1). Although speculative at this moment, it may provide a working hypothesis to help identify the involvement of NO in the events contributing to the vascular derangement of sepsis.

Fig. 1
Fig. 1:
Speculative time course of NO-dependent vascular changes in septic shock. After an inflammatory stimulus, increased NOS-2 expression and activity produces high NO levels, which are implicated in vascular reactivity changes such as loss in phenylephrine response and increase in vasodilator response to NO donors and bradykinin. These combined effects contribute to the impairment of tissue perfusion. High NO production is also responsible by decrease in sGC activity/content. The recovery of sGC response is dependent onde novo synthesis of the enzyme. NOS inhibitors are effective in restoring vascular reactivity only when administered early in sepsis, when NOS-2 expression and NO production are at their peak. On the other hand, sGC inhibitors are effective when injected late in sepsis, when sGC activity/content are higher. Potassium channels in turn seem to be involved in NO effects in both early and late periods of sepsis.

Concluding remarks

Although it is well established that NO is involved in the four pillars of sepsis (inflammatory, immunological, cardiovascular, and infectious), many questions still remain unanswered concerning the role of NO in vascular changes during sepsis and septic shock. Thus, understanding the relationship between NO and its effectors, especially sGC and potassium channels, may provide new insights and may provide new directions for the management of sepsis and septic shock.


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Potassium channels; guanylate cyclase; blood pressure; vasoplegia; septic shock

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