Sepsis and septic shock are associated with mortality rates of up to 50-70% and the majority of patients die due to complications of multiple organ failure. The cyclic GMP (cGMP) producing enzyme soluble guanylate cyclase (sGC) is crucially involved in the maintenance of (micro)vascular homeostasis, cardiac function and, consequently, organ function. Reactive oxygen species (ROS) can inactivate sGC by oxidizing the iron in the haem group, the resulting haem-free sGC can be reactivated by BAY 58-2667 (Cinaciguat) (Evgenov et al., 2006). We tested BAY 58-2667 in a murine model of endotoxic shock because of its assumed specificity for tissues that are suffering from (metabolic) hypoxia and oxidative stress. To induce shock, mice were injected i.v. with 190-220 µg E. coli lipopolysaccharide (LPS). We report that post-treatment with BAY 58-2667 can protect against endotoxic shock-induced progressive hypothermia (compared to vehicle controls, repeated measure ANOVA, n = 15) and mortality (66% vs. 0% survival rate for vehicle controls, log-rank test, n = 15), which was associated with reduced cardiomyocyte apoptosis (assessed by TUNEL assay, 77.9 + 11.73 (mean + SEM) vs. 47.9 + 8.9 TUNEL positive cells, normalized over surface area, one-way ANOVA). The sGC stimulator BAY 41-2272 and phosphodiesterase 5 (PDE5) inhibitor Sildenafil did not have a beneficial effect on either LPS-induced morbidity or mortality. Furthermore, we assessed mean arterial pressure (MAP), heart rate (HR) and BP variability (BPV) indices continuously in conscious, freely moving mice. Mice were anaesthetized with isoflurane and PA-C10 radio-transmitters (Data Sciences International) were implanted. MAP and HR were both significantly decreased for 180 min post-treatment compared to vehicle controls (linear mixed model). Linear (normalized low frequency, LF (nu)) and nonlinear (detrended fluctuation analysis, DFA) indices of BPV were calculated in Labchart (ADInstruments) and software from the PhysioNet toolkit (Goldberger et al., 2000). The difference in BPV index trends was examined 40 min pre-treatment vs. 40 min post-treatment. Treatment with BAY 58-2667 increased LF (nu) and DFA scaling factors, compared to vehicle controls (n = 4), indicative for improved communication between the autonomic nervous system and the heart. Our results emphasize the pivotal role of sGC signaling in endotoxic shock. Stabilization of sGC function with BAY 58-2667 can prevent mortality induced by endotoxic shock when given in the correct treatment window, which probably depends on the dynamics of the haem-free sGC pool, in turn influenced by ROS production. We speculate that the effect of BAY 58-2667 on microcirculatory perfusion and (metabolic) hypoxia supports organ function by recoupling inter-organ communication pathways.