ACTIVATION OF VASCULAR SMOOTH MUSCLE K+ CHANNELS BY ENDOTHELIUM-DERIVED RELAXING FACTORS

1. Endothelium‐derived relaxing factors (EDRF), including nitric oxide (NO), prostacyclin (PGI2) and an as yet uncharacterized endothelium‐derived hyperpolarizing factor (EDHF), are now recognized to induce relaxation of vascular smooth muscle, in part via the activation of K+ channels. 2. Experiments using selective K+ channel blockers, including iberiotoxin (IbTX), glibenclamide, apamin and 4‐aminopyridine (4‐AP) to inhibit endothelium‐induced relaxation suggest that more than one type of K+ channel may be involved, depending on the species and tissue, including: (i) large conductance Ca2+‐activated (BKCa) channels; (ii) ATP‐sensitive (KATP) channels; (iii) small conductance Ca2+‐activated (SKCa) channels; and (iv) voltage‐gated (Kv) K+ channels. 3. Recent observations suggest a role for Kv channels in some vessels based on a sensitivity of NO‐ and PGI2‐mediated relaxations to 4‐AP, as well as a complete suppression of EDHF‐ dependent relaxation by a combination of charybdotoxin (ChTX) and apamin but not IbTX and apamin. 4. The molecular identity of the K+ channels affected by EDRF is not well characterized. Recently, findings indicate that the pore‐forming α‐subunit tetramers of vascular smooth muscle BKCa channels are due to the expression of the so‐called Slo channel gene. The identities of the KATP, SKCa and Kv channels involved in endothelium‐dependent vasodilation are not known. 5. The component of whole‐cell Kv current affected by PGI2 may be due to slowly inactivating, 4‐AP‐sensitive, 15 pS delayed‐rectifier K+ channels (KDR); the activity of these channels in vascular myocytes is increased by forskolin and protein kinase A (PKA) and rabbit portal vein Kv1.5 pore‐forming α‐subunits, which appear to be a component of native KDR current and possess consensus phosphorylation sequences for PKA.