Figure 50-10 Mechanisms of action of glyceryl trinitrate (GTN). GTN is metabolized to NO, which stimulates the synthesis of cyclic guanosine monophosphate (cGMP). In turn, cGMP reduces cytoplasmic Ca²⁺ by inhibiting inflow and stimulating mitochondrial uptake, which causes relaxation of smooth muscle cells. The role of Ca²⁺ -activated K⁺ currents is also being investigated; by inducing hyperpolarization of the cellular membrane, they might contribute to the limitation of Ca²⁺ entry into smooth muscle cells, and in endothelial cells, they might inhibit ^• O₂ ^- production. By promoting Ca²⁺ uptake, antithrombin II (AT II) can increase cytoplasmic Ca²⁺ and induce Ca²⁺ -dependent phosphodiesterase 1A1 (PDE1A1). This may lead to reduced cGMP and cGK activity, thus providing an elegant explanation for both nitrate tolerance and increased sensitivity to AT III. Some evidence supports a redox sensitivity of all enzymes involved in these procedures. GTP, guanosine triphosphate; sGC, soluble guanylyl cyclase; cGK, cGMP-dependent protein kinase. (Redrawn from Gori T, Parker JD: Nitrate tolerance. A unifying hypothesis. Circulation 106:2510–2513, 2002.)