Use of intermediate/small conductance calcium-activated potassium-channel activator for endothelial protection

Endothelial dysfunction occurs in hypoxia-related states such as ischemic heart disease or heart surgery. Intermediate- and small-conductance calcium-activated potassium channels (IKCa and SKCa) are closely related to endothelium-dependent hyperpolarizing factor-mediated endothelial function. However, the status of these KCa under hypoxia is unknown. We investigated whether endothelial dysfunction under hypoxic state is related to the alterations of IKCa and SKCa and whether use of IKCa/SKCa activator may protect endothelium from hypoxia-reoxygenation injury.

Isometric tension measurement, patch-clamp technique, intracellular membrane potential recording, and molecular methods were used to study porcine coronary arteries and endothelial cells.

Hypoxia-reoxygenation (60-30 minutes) decreased endothelium-dependent hyperpolarizing factor-mediated relaxation at normothermia in Krebs solution (43.3%±6.3% vs 82.3%±2.9%) and in St Thomas' Hospital cardioplegic solution (28.9%±1.8% vs 78.1%±3.0%) (P<.001) as well as at hypothermia in St Thomas' Hospital solution (43.1%±2.6%, P<.001). Hypoxia-reoxygenation markedly reduced endothelial IKCa (2.8±0.6 vs 6.9±0.6 pA/pF) and SKCa currents (1.5±0.3 vs 4.3±0.4 pA/pF) (P<.05) and downregulated endothelial IKCa expression. IKCa/SKCa activator 1-ethyl-2-benzimidazolinone enhanced K+ current in endothelial cells that was blunted by hypoxia. Further, 1-ethyl-2-benzimidazolinone restored (P<.001) endothelium-dependent hyperpolarizing factor-mediated relaxation with hyperpolarization recovered from 6.0±0.3 to 7.8±0.4 mV (P<.05).

In porcine coronary arteries, hypoxia markedly reduced endothelial K+ currents related to IKCa and SKCa with downregulation of protein expression and endothelium-derived hyperpolarizing factor function. IKCa/SKCa activator may preserve endothelium-dependent hyperpolarizing factor-mediated relaxation with enhancement of K+ current in endothelial cells and cellular membrane potential hyperpolarization in smooth muscle cells and may become a new strategy to protect coronary endothelium in cardiac surgery or transplantation.