Endothelium-derived hydrogen sulfide acts as a hyperpolarizing factor and exerts neuroprotective effects via activation of large-conductance Ca2+-activated K+ channels

Background and Purpose Endothelium-derived hyperpolarizing factor (EDHF) has been suggested as a therapeutic target for vascular protection against ischaemic brain injury. However, the molecular entity of EDHF and its action on neurons remains unclear. This study was undertaken to demonstrate whether the hydrogen sulfide (H2S) acts as EDHF and exerts neuroprotective effect via large-conductance Ca2+-activated K+ (BKCa/K(Ca)1.1) channels. Experimental Approach The whole-cell patch-clamp technology was used to record the changes of BKCa currents in rat neurons induced by EDHF. The cerebral ischaemia/reperfusion model of mice and oxygen-glucose deprivation/reoxygenation (OGD/R) model of neurons were used to explore the neuroprotection of EDHF by activating BKCa channels in these neurons. Key Results Increases of BKCa currents and membrane hyperpolarization in hippocampal neurons induced by EDHF could be markedly inhibited by BKCa channel inhibitor iberiotoxin or endothelial H2S synthase inhibitor propargylglycine. The H2S donor, NaHS-induced BKCa current and membrane hyperpolarization in neurons were also inhibited by iberiotoxin, suggesting that H2S acts as EDHF and activates the neuronal BKCa channels. Besides, we found that the protective effect of endothelium-derived H2S against mice cerebral ischaemia/reperfusion injury was disrupted by iberiotoxin. Importantly, the inhibitory effect of NaHS or BKCa channel opener on OGD/R-induced neuron injury and the increment of intracellular Ca2+ level could be inhibited by iberiotoxin but enhanced by co-application with L-type but not T-type calcium channel inhibitor. Conclusion and Implications Endothelium-derived H2S acts as EDHF and exerts neuroprotective effects via activating the BKCa channels and then inhibiting the T-type calcium channels in hippocampal neurons.

Automated summary

This study demonstrates that hydrogen sulfide acts as endothelium-derived hyperpolarizing factor (EDHF) and exerts neuroprotective effects by activating BKCa channels in hippocampal neurons.