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

Abstract

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 Ca(2+)-activated (BKCa) channels; (ii) ATP-sensitive (KATP) channels; (iii) small conductance Ca(2+)-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 alpha-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 alpha-subunits, which appear to be a component of native KDR current and possess consensus phosphorylation sequences for PKA.

The Proteome of Mouse Cerebral Arteries

“…34 Each of the endotheliumderived relaxing factors, namely NO, prostacyclin, and endothelium-derived hyperpolarizing factor, can activate one or several types of SMC K þ channels. 35 We detected three NOSs in our arterial data set, specifically the previously mentioned NOS1 (or nNOS), as well as NOS2 (or iNOS) and NOS3 (or eNOS).…”

Diabetes-related changes in cAMP-dependent protein kinase activity and decrease in relaxation response in rat mesenteric artery

“…Activation of PKA in vascular smooth muscle cells by an elevated cytoplasmic cAMP concentration results in relaxation as a result of phosphorylations both of effector proteins, including myosin light chain kinase, and of the ion channels that regulate the cytosolic Ca 2ϩ concentration and hyperpolarization (e.g., K ϩ channels) (41,52,58). Furthermore, PKA-mediated phosphorylations underpin the EDHF phenomenon in several arteries (21,56).…”

Effect ofCrataegusUsage in Cardiovascular Disease Prevention: An Evidence-Based Approach

“…Moreover, it preserves endothelium-dependent relaxation and vascular contraction in STZ-induced diabetes, possibly by reducing iNOS expression in the aorta, by decreasing plasma levels of TNF- α and IL-6, and by preventing lipid peroxidation [52]. There is evidence that NO may increase activation of both the ATP-dependent K + -channel and the Ca 2+ -dependent K + -channel in vascular smooth muscle cells [53]. Similar experiment showed that procyanidins in Crataegus extract may be responsible for the endothelium-dependent NO-mediated relaxation, possibly via activation of tetraethylammonium sensitive K + channels in isolated rat aorta [54].…”