Hydrogen sulfide activates Ca2+ sparks to induce cerebral arteriole dilatation

摘要

Hydrogen sulfide (H2S) is a gaseous vasodilator produced by endothelial cells. Mechanisms by which H2S induces vasodilatation are unclear. We tested the hypothesis that H2S dilates cerebral arterioles by modulating local and global intracellular Ca²⁺ signals in smooth muscle cells. High-speed confocal imaging revealed that Na2S, an H2S donor, increased Ca²⁺ spark frequency ∼1.43-fold and decreased global intracellular Ca²⁺ concentration ([Ca²⁺]i) by ∼37 nm in smooth muscle cells of intact piglet cerebral arterioles. In contrast, H2S did not alter Ca²⁺ wave frequency. In voltage-clamped (−40 mV) cells, H2S increased the frequency of iberiotoxin-sensitive, Ca²⁺ spark-induced transient Ca²⁺-activated K⁺ (KCa) currents ∼1.83-fold, but did not alter the amplitude of these events. H2S did not alter the activity of single KCa channels recorded in the absence of Ca²⁺ sparks in arteriole smooth muscle cells. H2S increased SR Ca²⁺ load ([Ca²⁺]SR), measured as caffeine (10 and 20 mm)-induced [Ca²⁺]i transients, ∼1.5-fold. H2S hyperpolarized (by ∼18 mV) and dilated pressurized (40 mmHg) cerebral arterioles. Iberiotoxin, a KCa channel blocker, reduced H₂S-induced hyperpolarization by ∼51%. Iberiotoxin and ryanodine, a ryanodine receptor channel inhibitor, reduced H₂S-induced vasodilatation by ∼38 and ∼37%, respectively. In summary, our data indicate that H₂S elevates [Ca²⁺]_SR, leading to Ca²⁺ spark activation in cerebral arteriole smooth muscle cells. The subsequent elevation in transient K_Ca current frequency leads to membrane hyperpolarization, a reduction in global [Ca²⁺]_i and vasodilatation.