Endothelial potassium channels, endothelium-dependent hyperpolarization and the regulation of vascular tone in health and disease

Authors


  • Presented at the Australian Physiological and Pharmacological Society Symposium Potassium Channels and Endothelium-Derived Hyperpolarizing Factor: Physiological and Clinical Roles, September 2003. The papers in these proceedings were peer reviewed under the supervision of the APPS Editor. The papers are being published with the permission of the APPS and were initially published on the APPS website (http://www.apps.org.au).

Dr HA Coleman, Department of Physiology, Monash University, Victoria 3800, Australia. Email: harry.coleman@med.monash.edu.au

Summary

1. The elusive nature of endothelium-derived hyperpolarizing factor (EDHF) has hampered detailed study of the ionic mechanisms that underlie the EDHF hyperpolarization and relaxation. Most studies have relied on a pharmacological approach in which interpretations of results can be confounded by limited specificity of action of the drugs used. Nevertheless, small-, intermediate- and large-conductance Ca2+-activated K+ channels (SKCa, IKCa and BKCa, respectively) have been implicated, with inward rectifier K+ channels (KIR) and Na+/K+-ATPase also suggested by some studies.

2. Endothelium-dependent membrane currents recorded using single-electrode voltage-clamp from electrically short lengths of arterioles in which the smooth muscle and endothelial cells remained in their normal functional relationship have provided useful insights into the mechanisms mediating EDHF. Charybdotoxin (ChTx) or apamin reduced, whereas apamin plus ChTx abolished, the EDHF current. The ChTx- and apamin-sensitive currents both reversed near the expected K+ equilibrium potential, were weakly outwardly rectifying and displayed little, if any, time- or voltage-dependent gating, thus having the biophysical and pharmacological characteristics of IKCa and SKCa channels, respectively.

3. The IKCa and SKCa channels occur in abundance in endothelial cells and their activation results in EDHF-like hyperpolarization of these cells. There is little evidence for a significant number of these channels in healthy, contractile vascular smooth muscle cells.

4. In a number of blood vessels in which EDHF occurs, the endothelial and smooth muscle cells are coupled electrically via myoendothelial gap junctions. In contrast, in the adult rat femoral artery, in which the smooth muscle and endothelial layers are not coupled electrically, EDHF does not occur, even though acetylcholine evokes hyperpolarization in the endothelial cells.

5. In vivo studies indicate that EDHF contributes little to basal conductance of the vasculature, but it contributes appreciably to evoked increases in conductance.

6. Endothelium-derived hyperpolarizing factor responses are diminished in some diseases, including hypertension, pre-eclampsia and some models of diabetes.

7. The most economical explanation for EDHF in vitro and in vivo in small vessels is that it arises from the activation of IKCa and SKCa channels in endothelial cells. The resulting endothelial hyperpolarization spreads via myoendothelial gap junctions to result in the EDHF-attributed hyperpolarization and relaxation of the smooth muscle.

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