Details are shown in Table 3. MAPK Inhibitor Library (Fisher’s exact test) Our results did not confirm our hypothesis that an ADMA-induced inhibition of NOS leads to an increase in PAP and to an increased susceptibility to AMS. On the contrary, our tests suggested the exact opposite as described above. The increase in PAP thus may not be caused by an increase in ADMA. Against our assumptions, ADMA was not confirmed as a potential trigger to generate

a PAP value of higher than 40 mmHg, which is considered to be the critical threshold for the development of HAPE. In summary, the reported results show a statistically significant negative correlation of Δ-ADMA and PAP (ρ: −0.74; p ≤ 0.01) and altitude symptoms (ρ: −0.8; p ≤ 0.01). In addition, the measurement of Δ-ADMA under conditions

of acute hypoxia (at 4000 m) is also a suitable method for identifying individuals who are likely to develop critical PAP of more than 40 mmHg (ϕ: 0.69; p ≤ 0.05) and who are susceptible to AMS (LLS ≥ 5) (ϕ: 0.82; p ≤ 0.02). Those at risk can be identified as early as 2 hours after the start of exposure to hypoxia (at an altitude of 4000 m). It is not the absolute ADMA level but rather the change (increase or decrease) in ADMA against the baseline level that plays a key role Opaganib clinical trial in this context. In our collective results, the Δ-ADMA value after 2 hours of hypoxia can predict the development of AMS with a sensitivity of 80% and a specificity of 100%. If PAP increases to more than 40 mmHg within 2 hours of exposure, the occurrence of AMS is likely to be expected in 100% of the cases. In their study on the course of PAP during altitude exposure, Dorrington and colleagues[15] indirectly confirmed that prognostic information can be obtained after such a short period of exposure. Using right-heart catheterization, these authors showed that a maximum PAP level was reached as early as 2 hours after the onset of exposure to hypoxic conditions. Our results confirmed the findings reported by Song and colleagues.[16] These authors exposed mice to previously lethal conditions—a BCKDHB fraction of oxygen (FO2)

of 0.046%—and expected that NOS inhibition (eg, by ADMA) would decrease hypoxic tolerance. Contrary to their original hypothesis, they found that hypoxic tolerance improved greatly and some of the mice that were treated with ADMA even survived. As synthetic NOS inhibitors such as Nω-nitro- l-arginine (l-NNA) also improved hypoxic tolerance, these unexpected results confirmed that it was this NOS-mediated function in the systemic response to acute hypoxia rather than a nonspecific effect of ADMA that was responsible for the improvement in hypoxic tolerance. The administration of the NO donor 3-morpholinosydnoeimine (SIN-1) attenuated the increase in hypoxic tolerance produced by l-NNA. This, too, was contrary to the initial hypothesis.