Potassium channels in the peripheral microcirculation

Abstract

Vascular smooth muscle (VSM) cells, endothelial cells (EC), and pericytes that form the walls of vessels in the microcirculation express a diverse array of ion channels that play an important role in the function of these cells and the microcirculation in both health and disease. This brief review focuses on the K+ channels expressed in smooth muscle and endothelial cells in arterioles. Microvascular VSM cells express at least four different classes of K+ channels, including inward-rectifier K+ channels (Kin), ATP-sensitive K+ channels (KATP), voltage-gated K+ channels (Kv), and large conductance Ca2+-activated K+ channels (BKCa). VSM KIR participate in dilation induced by elevated extracellular K+ and may also be activated by C-type natriuretic peptide, a putative endothelium-derived hyperpolarizing factor (EDHF). Vasodilators acting through cAMP or cGMP signaling pathways in VSM may open KATP, Kv, and BKCa, causing membrane hyperpolarization and vasodilation. VSMBKc. may also be activated by epoxides of arachidonic acid (EETs) identified as EDHF in some systems. Conversely, vasoconstrictors may close KATP, Kv, and BKCa through protein kinase C, Rho-kinase, or c-Src pathways and contribute to VSM depolarization and vasoconstriction. At the same time Kv and BKCa act in a negative feedback manner to limit depolarization and prevent vasospasm. Microvascular EC express at least 5 classes of K+ channels, including small (sKCa) and intermediate(IKCa) conductance Ca2+-activated K+ channels, Kin, KATP, and Kv. Both sK and IK are opened by endothelium-dependent vasodilators that increase EC intracellular Ca2+ to cause membrane hyper-polarization that may be conducted through myoendothelial gap junctions to hyperpolarize and relax arteriolar VSM. KIR may serve to amplify sKCa- and IKCa-induced hyperpolarization and allow active transmission of hyperpolarization along EC through gap junctions. EC KIR channels may also be opened by elevated extracellular K+ and participate in K+-induced vasodilation. EC KATP channels may be activated by vasodilators as in VSM. Kv channels may provide a negative feedback mechanism to limit depolarization in some endothelial cells.

Figure 1

Ion channels expressed in arteriolar smooth muscle cells. Schematic diagram indicating the families of ion channels expressed in smooth muscle cells in the wall of arterioles. Current evidence (see text for details and references) indicate that arteriolar smooth muscle cells express inward rectifier K⁺ channels, ATP-sensitive K⁺ channels (K_ATP), several different types of voltage-gated K⁺ channels (K_V), one or more types of calcium-activated K⁺ channels (K_Ca), one or more types of voltage-gated Ca²⁺ channels (VGCC), two or more types of Cl⁻ channels (CLC), and several different types of nonselective cation channels (NSCC) likely from the transient receptor potential (Trp) family of channels. Intracellular ion channels include Ca²⁺-activated Ca²⁺ release channels (ryanodine receptors, RYR) and inositol 3,4,5-trisphosphate receptors (IP₃R). It should also be noted that other channels also are likely expressed in intracellular membranes, including those of mitochondria (not shown).

Figure 2

Potassium channels regulate arteriolar smooth muscle tone by affecting membrane potential. Schematic diagram of an arteriolar muscle cell and cross sections of arterioles with open or closed K⁺ channels. VGCC, voltage-gated Ca²⁺ channel.

Figure 3

Ion channels expressed in arteriolar endothelial cells. Schematic of a longitudinal section of an arteriole showing cross sections of endothelial cells and smooth muscle cells. Ion channels expressed by microvascular endothelial cells include ATP-sensitive K⁺ channels (K_ATP), voltage-gated K⁺ channels (K_V), inward rectifier K⁺ channels (K_IR), small conductance (sK_Ca) and intermediate conductance (IK_Ca) Ca⁺-activated K⁺ channels, and several types of non-selective cation channels (NSCC), likely from the transient receptor potential (Trp) family of channels. Intracellular ion channels include IP₃ receptors (IP₃R). Also shown are pathways for activation of endothelial K⁺ channels leading to endothelial membrane hyperpolarization (see text for references). Agonists such as acetylcholine, substance P, or bradykinin bind to G-protein coupled receptors (G_q/11) and activate phospholipase Cβ (PLCβ) that acts on membrane phospholipids (PIP₂) to form IP₃. This second messenger binds to IP₃ receptors (IP₃R) in the membrane of the smooth endoplasmic reticulum, releasing stored Ca²⁺. Release of Ca²⁺ from intracellular stores, as well as G-protein-mediated events and activation of other signaling cascades open nonselective cation channels (NSCC), allowing extracellular Ca⁺² to diffuse into the cells. Release of Ca²⁺ and increased Ca²⁺ influx increase intracellular Ca²⁺, leading to formation of endothelium derived autacoids such as NO, PGI₂ and epoxides of arachidonic acid (EETS) (not shown in figure). Elevated intracellular Ca²⁺ also activates IK_Ca and/or sK_Ca channels, leading to K⁺ efflux and membrane hyperpolarization. The K⁺ released through these channels and the membrane hyperpolarization may activate outward currents through K_IR channels, supporting the hyperpolarization. Because cells in the walls of arterioles are coupled by gap junctions, the endothelial cell hyperpolarization may be transmitted to other endothelial cells and to smooth muscle cells, leading to smooth muscle hyperpolarization, closure of voltage-gated Ca²⁺ channels (VGCC), a reduction in intracellular Ca²⁺, and vasodilation. Transmission of hyperpolarization through gap junctions to adjacent endothelial cells also may activate K_IR channels in these cells and allow conduction of hyperpolarizing signals for long distances along the endothelium.

Figure 4

Inward rectifier K⁺ (K_IR) channel currents in arteriolar endothelial cells. Data are means ± SE (n = 5). Ba²⁺-sensitive (100 μM) difference currents measured in the presence of 5 or 15 mM K⁺ in the extracellular fluid as indicated. Endothelial cells were isolated enzymatically from hamster cremaster arterioles and membrane currents studied using the amphotericin B perforated patch technique as described previously for arteriolar smooth muscle cells (72). Note that at normal extracellular K⁺ (5 mM), at the resting membrane potential of these cells (−30 mV), there is little or no outward current. However, with an increase in extracellular K⁺, the current–voltage relationship shifts to the right such that outward current through the K_IR channels is present. This would tend to hyperpolarize the cells toward, in this case, −45 mV. Note also that in physiological K⁺ (5 mM), membrane hyperpolarization induced by opening of other K⁺ channels could recruit outward current through K_IR channels, amplifying the original hyperpolarization.