Figure 15-38 The Ca²⁺/nitric oxide (NO)/cGMP pathway and the relaxation of vascular smooth muscle. Nitric oxide is synthesized in endothelial cells in response to activation of acetylcholine GPCRs, phospholipase C, and the subsequent elevation in cytosolic Ca²⁺ (steps 1–4). NO diffuses locally through tissues and activates an intracellular NO receptor with guanylyl cyclase activity in nearby smooth muscle cells 5. The resulting rise in cGMP 6 activates protein kinase G 7, leading to relaxation of the muscle and thus vasodilation 8. PPi = pyrophosphate. See C. S. Lowenstein et al., 1994, Ann. Intern. Med. 120:227, and H. K. Surks, 2007, Circ. Res. 101:1078.