Tuning Electrical Conduction Along Endothelial Tubes of Resistance Arteries Through Ca ²⁺ -Activated K ⁺ Channels

Abstract

Rationale Electrical conduction through gap junction channels between endothelial cells of resistance vessels is integral to blood flow control. Small and intermediate-conductance Ca2+-activated K+ channels (SKCa/IKCa) initiate electrical signals in endothelial cells but it is unknown whether SKCa/IKCa activation alters signal transmission along the endothelium. Objective We tested the hypothesis that SKCa/IKCa activity regulates electrical conduction along the endothelium of resistance vessels. Methods and Results Freshly isolated endothelial cell tubes (60 μm wide; 1–3mm long; cell length, ~35 μm) from mouse skeletal muscle feed (superior epigastric) arteries were studied using dual intracellular microelectrodes. Current was injected (±0.1–3 nA) at Site 1 while recording membrane potential (Vm) at Site 2 (separation distance = 50–2000 μm). SKCa/IKCa activation (NS309, 1 μmol/L) reduced the change in Vm along endothelial cell tubes by ≥50% and shortened the electrical length constant (λ) from 1380 to 850 μm (P<0.05) while intercellular dye transfer (propidium iodide) was maintained. Activating SKCa/IKCa with acetylcholine or SKA-31 also reduced electrical conduction. These effects of SKCa/IKCa activation persisted when hyperpolarization (>30 mV) was prevented with 60 mM [K+]o. Conversely, blocking SKCa/IKCa (apamin + charybdotoxin) depolarized cells by ~10 mV and enhanced electrical conduction (i.e., changes in Vm) by ~30% (P<0.05). Conclusions These findings illustrate a novel role for SKCa/IKCa activity in tuning electrical conduction along the endothelium of resistance vessels by governing signal dissipation through changes in membrane resistance. Voltage-insensitive ion channels can thereby tune intercellular electrical signaling independent from gap junction channels.

Origins of variation in conducted vasomotor responses

“…The surplus of charge obtained by the local inhibition of few channels induces a stronger local V m -response that in turn opens other ion channels and consequently limits the gain in longitudinal spread of charge (compared to the whole vessel, the small decrease in local charge dissipation is negligible). On the other hand, a global activation or inactivation of these ion channels across the whole vessel had a large impact on electrical spread (dashed black lines) as previously described [2,19,39].…”

“…2c and 5). In isolated EC tubes, current in the nano-ampere range can be easily injected into a single EC [2], demonstrating that gap junctions are generally open pores with high current conductance in the EC layer.…”

“…On the other hand, a global alteration of one or more ion channels may significantly change conduction efficiency (Fig. 7) as previously described [2,19]. Modulation of ion transporters may appear in two principally different flavors: (1) Modulation of constitutively active ion transporter(s) that maintain the resting potential, e.g., the Na/K exchanger or non-specification channels.…”

“…Global application of such an agonist changes the endogenous V m,rest of the cell layer and may have pronounced effect on communication along the vessel (Fig. 4) [2,19]. For instance, although different isoforms of (e.g., T-and L-types) VGCCs exist, the open probability for all isoforms increases approximately in the same V m -range, i.e., a global depolarization to ∼ −30 mV not only produce constriction but also increase the sensitivity to additional depolarizing stimuli.…”

“…The mechanism is mediated by fast electrical signaling through intercellular gap junctions within the vascular wall and is independent of perivascular nerves or blood flow and pressure [2,14,16,39]. The CVR is elicited by either mechanical or pharmacological stimuli that opens specific ion channels in the plasma membrane of vascular cells.…”