Figure 1.

Synthesis of nitric oxide (NO) by endothelial cells. NO is released by the action of endothelial NO synthase (eNOS) on its substrate, L-arginine. For this reaction, several cofactors, such as tetrahydrobiopterin (BH₄), oxygen (O₂), and nicotinamide adenine dinucleotide phosphate (NADPH) are required. eNOS is activated by calcium-dependent and -independent pathways. Intracellular Ca is increased as a response to the function of NO agonists (including acetylcholine (Ach), bradykinin (BK), adenosine triphosphate (ATP), and adenosine diphosphate (ADP), serotonin, thrombin, and histamine) or by influx into the endothelial cell following the opening of the store-operated calcium channel (SOC) and other calcium permeable channels in the plasma membrane. Ca binds to calmodulin, and this complex dissociates eNOS from the inhibitor caveolin-1, located in the caveolae. eNOS can also be activated by the calcium-independent pathway of post-translational phosphorylation, which is triggered as a response to shear stress and the function of growth factors and hormones. After NO is generated, it diffuses across the membrane of smooth muscle cells and activates the guanylyl cyclase (sGC), which catalyzes the reaction from guanosine triphosphate (GTP) to cyclic guanosine monophosphate cyclic guanosine monophosphate (cGMP). The effect of this reaction is the transportation of calcium out of the cell, which downregulates the activity of myosin light chain kinase (MLCK), causing relaxation of the vascular smooth muscle cell. Abbreviations: Ach, acetylcholine; ADP, adenosine diphosphate; ATP, adenosine triphosphate; BH₄, tetrahydrobiopterin; BK, bradykinin; Ca, calcium; cGMP, cyclic guanosine monophosphate; eNOS, endothelial NO synthase; GTP, guanosine triphosphate; MLCK, myosin light chain kinase; NADPH, nicotinamide adenine dinucleotide phosphate; NO, nitric oxide; O2, oxygen; R, receptor; sGC, guanylyl cyclase; SOC, the store-operated calcium channel.