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Figure 8 Schematic diagram depicting the mechanisms underlying nitroglycerin (NTG)-induced relaxation (A) and the vascular consequences of NTG-induced vascular peroxynitrite formation (B). (A) Short-term NTG treatment causes vasorelaxation by releasing the vasoactive metabolite nitric oxide (NO), which, in turn, stimulates both soluble guanylyl cyclase (sGC) and release of prostacyclin (PGI₂). Activation of sGC and adenylyl cyclase (AC) increases the formation of the second messengers cyclic guanosine monophosphate (cGMP) and cAMP. Signaling pathways activated by cAMP and cGMP may interact at different levels. Subsequent activation of cGMP- and cAMP-dependent kinase (cGK-I and cAK) will induce vasorelaxation. Activation of cyclic guanosine monophosphate-dependent kinase-I (cGK-I) and, to some extent, cAK will cause phosphorylated vasodilator-stimulated phosphoprotein (P-VASP) at serine 239. VASP is also phosphorylated at serine 157, which is primarily mediated by cAK and which was not analyzed in this study. (B) Long-term treatment with NTG stimulates the production of reactive oxygen species such as peroxynitrite (ONOO^–). Peroxynitrite may, in turn, induce tolerance via inhibiting the activity of the NTG-metabolizing enzyme (mitochondrial aldehyde dehydrogenase). Peroxynitrite may also cause endothelial dysfunction via oxidization of the NOSIII co-factor tetrahydrobiopterin and by tyrosine nitration of PGI₂-S associated with decreased P-VASP.