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

Objectives Endothelial dysfunction occurs in hypoxia-related states such as ischemic heart disease or heart surgery. Intermediate- and small-conductance calcium-activated potassium channels (IK Ca and SK Ca ) are closely related to endothelium-dependent hyperpolarizing factor–mediated endothelial function. However, the status of these K Ca under hypoxia is unknown. We investigated whether endothelial dysfunction under hypoxic state is related to the alterations of IK Ca and SK Ca and whether use of IK Ca /SK Ca activator may protect endothelium from hypoxia–reoxygenation injury. Methods Isometric tension measurement, patch-clamp technique, intracellular membrane potential recording, and molecular methods were used to study porcine coronary arteries and endothelial cells. Results 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 P Ca (2.8 ± 0.6 vs 6.9 ± 0.6 pA/pF) and SK Ca currents (1.5 ± 0.3 vs 4.3 ± 0.4 pA/pF) ( P Ca expression. IK Ca /SK Ca activator 1-ethyl-2-benzimidazolinone enhanced K + current in endothelial cells that was blunted by hypoxia. Further, 1-ethyl-2-benzimidazolinone restored ( P P Conclusions In porcine coronary arteries, hypoxia markedly reduced endothelial K + currents related to IK Ca and SK Ca with downregulation of protein expression and endothelium-derived hyperpolarizing factor function. IK Ca /SK Ca 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.