Divya Gupta et al. JCHF 2013;1:183-191 Tolerance and Pseudotolerance With Nitrate Therapy Nitrate use leads to neurohormonal activation, which results in intravascular expansion through increased sodium and water retention (pseudotolerance). Later during therapy, changes in endothelial and smooth muscle cells function resulting in vascular dysfunction (tolerance). These changes include: 1) activation of NADPH oxidase by angiotensin II through protein kinase C, which in turn results in superoxide (O2–) production; superoxide results in vasoconstriction through endothelin-1 and protein kinase C; 2) protein kinase C directly inhibits nitric oxide synthase; 3) reduced expression of GTP-cyclohydrolase and peroxynitrite-induced oxidation of tetrahydrobiopterin causes limited tetrahydrobiopterin availability, which in turn causes uncoupling of endothelial nitric oxide synthase, resulting in superoxide production and nitric oxide anions (NO–); nitric oxide anions through peroxynitrite cause inhibition of prostacyclin synthase resulting in reduced prostacyclin levels; 4) impaired bioactivation of nitroglycerin (NTG) caused by inhibition of aldehyde dehydrogenase results in O2– production, which in turn inhibits smooth muscle soluble guanylate cyclase both directly and through peroxynitrite; and 5) cyclic-guanosine monophosphate (cGMP) vasodilatory properties are diminished secondary to cGMP inactivation by phosphodiesterases and low cGMP production because of the inhibition of soluble guanylate cyclase. Divya Gupta et al. JCHF 2013;1:183-191 American College of Cardiology Foundation