Figure 50-12 Diagram describing the oxidative pathway for the development of nitrate tolerance. Both endothelial and smooth muscle cells are involved in these processes. Increased free radical generation, increased production and responsiveness to angiotensin II (AT II), and L-arginine depletion may result in nitric oxide synthase (NOS) uncoupling and further production of ^• O₂ ^- and peroxynitrite. BH₄ , tetrahydrobiopterin; ET-1, endothelin-1; NADPH, reduced nicotinamide adenine dinucleotide phosphate; ^• O₂ ^- , superoxide anion; PKC, protein kinase C. (Redrawn from Gori T, Parker JD: The puzzle of nitrate tolerance. Pieces smaller than we thought? Circulation 106:2404–2408, 2002.)