Late, but Not Early, Inhibition of Soluble Guanylate Cyclase Decreases Mortality in a Rat Sepsis Model

Abstract

Overproduction of nitric oxide and activation of soluble guanylate cyclase (sGC) are important in sepsis-induced hypotension and hyporesponsiveness to vasoconstrictors. A time course of the expression and activity of sGC in a sepsis model [cecal ligation and puncture (CLP)] was evaluated in rats. Soluble GC ␣-1 and ␤-1 subunit mRNA levels increased in the lungs, but not in the aorta. However, in both tissues, the protein levels increased 24 h after sepsis and remained high for up to 48 h. Sodium nitroprusside-stimulated cGMP accumulation was higher 48 h after CLP in the lung and aorta. NOS-2 protein expression peaked 24 h after CLP, decreasing thereafter. The impact of inhibiting the expression of sGC early (8 h) or late (20 h) on vascular reactivity and the indexes of organ damage and mortality were also studied. Late administration of methylene blue (MB) or ODQ (1H-[1,2,4]-oxadiazole[4,3-a]quinoxalin-1-one) restored the blood pressure and vascular responsiveness to vasoconstrictors to normal levels but was ineffective in early sepsis. Late MB injection reduced the plasma levels of urea, creatinine, and lactate. MB improved the survival if administered late, but it increased the mortality when administrated early after sepsis onset. The increased sGC expression/ activity may be relevant for the late hypotension and hyporesponsiveness to vasoconstrictors in sepsis. In accordance, MB increased survival if administered in late sepsis, but not in early sepsis. Therefore, differential responsiveness to sGC during the course of sepsis may determine the success or failure of treatment with sGC inhibitors.Severe sepsis and septic shock are major causes of mortality in intensive care units (Vincent et al., 2006). The number of patients with severe sepsis and septic shock is increasing because of increased life expectancy and the rise in the number of immunocompromised patients, among other reasons (Bonde et al., 2006).Large amounts of nitric oxide (NO) are produced by NO synthase (NOS) 2 (inducible NOS) isoform in response to an injury in the vascular endothelium (Chin-Wei et al., 2008), vascular smooth muscle (Rees et al., 1990), and myocardium (Niu et al., 2008). Increased NO production contributes to some of the key features of septic shock, such as severe hypotension, vascular hyporesponsiveness toward vasoconstrictors, and myocardial dysfunction. NOS inhibition studies in sepsis are mostly based on in vitro or animal studies (for review, see Assreuy, 2006). To date, all the NOS inhibitors that have been tested in the clinical setting are nonselective for the three NOS isoforms, which causes undesired side effects, such as excessive vasoconstriction, which was the most likely reason for a phase III study with a NOS inhibitor in human sepsis to be interrupted (López et al., 2004).Soluble guanylate cyclase (sGC) is a key element in NO signaling. This enzyme is usually a heterodimer of ␣ and ␤ subunits, and it is activated by NO binding to its heme This work was supported by

Methylene Blue for Distributive Shock: A Potential New Use of an Old Antidote

“…One of these selective agents is methylene blue, which may restore vascular tone and improve tissue perfusion. There are multiple experimental models of septic shock that support the use of methylene blue in the treatment of refractory distributive shock [70][71][72][73][74][75][76]. The majority of clinical data on the use of methylene blue for such therapy is observational with case reports and small observational studies, but there are also small controlled clinical trials [77][78][79][80][81][82].…”

sGCα1β1attenuates cardiac dysfunction and mortality in murine inflammatory shock models

“…These dual effects of cGMP appear to depend, at least in part, on the timing of sGC inhibition: cGMP might be detrimental in one phase of inflammatory shock but protective in another (15,16). Alternatively, it cannot be excluded that the source of cGMP (sGC␣ 1 ␤ 1 or sGC␣ 1 ␤ 2 ) determines its impact on cardiac function.…”

Rapid NOS-1-derived nitric oxide and peroxynitrite formation act as signaling agents for inducible NOS-2 expression in vascular smooth muscle cells

“…Our group recently showed that the increase of NOS-1 expression during sepsis plays a role in hypotension and vascular dysfunction observed in this condition [16], since it is time-matched with the expression of the most important NO target, soluble guanylate cyclase, in vessels [52]. The up-regulation of both c-NOS has also been shown in different tissues of sepsis-bearing animals [52,53].…”