Multiplicity of mechanisms leading to endothelium-dependent hyperpolarization. The mechanism proposed by Matoba et al. (1) is highlighted. Substances such as acetylcholine (ACh), bradykinin (BK), and substance P (SP), through the activation of M₃-muscarinic, B₂-bradykinin, and NK₁-neurokinin receptor subtypes, respectively, and agents that increase intracellular calcium, such as the calcium ionophore A23187, release endothelium-derived hyperpolarizing factors. CaM, calmodulin; COX, cyclooxygenase; EET, epoxyeicosatrienoic acid; IP₃, inositol trisphosphate; GC, guanylate cyclase; NAPE, N-acylphosphatidylethanolamine; Hyperpol., hyperpolarization; NOS, NO synthase; O₂^•–, superoxide anions; PGI₂, prostacyclin; P450, cytochrome P450 monooxygenase; R, receptor; X, putative EDHF synthase. SR141716 is an antagonist of the cannabinoid CB₁ receptor subtype (CB₁). Glibenclamide (Glib) is a selective inhibitor of ATP-sensitive potassium channels (K⁺_ATP). Tetraethylammonium (TEA) and tetrabutylammonium (TBA) are nonspecific inhibitors of potassium channels when used at high concentrations (> 5 mM), while at lower concentrations (1–3 mM) these drugs are selective for calcium-activated potassium channels (K⁺_Ca2+). Iberiotoxin (IBX) is a specific inhibitor of large conductance K⁺_Ca2+. Charybdotoxin (CTX) is an inhibitor of large conductance K⁺_Ca2+, intermediate conductance K⁺_Ca2+ (IK_Ca2+), and voltage-dependent potassium channels. Apamin is a specific inhibitor of small conductance K⁺_Ca2+ (SK_Ca2+). Barium (Ba²⁺), in the micromolar range, is a specific inhibitor of the inward rectifier potassium channel (K_ir). GAP 27 (an eleven–amino acid peptide possessing conserved sequence homology to a portion of the second extracellular loop of connexin), 18α-glycyrrhetinic acid (αGA), and heptanol are gap junction uncouplers. Adapted from ref. 7.