Hydrogen sulfide dilates rat mesenteric arteries by activating endothelial large-conductance Ca~(2+)-activated K+ channels and smooth muscle Ca~(2+) sparks

摘要

Ca~(2+) sparks are spatially and temporally limited Ca~(2+)-release events from ryanodine receptor Ca~(2+)-release channels (RyR) in the sarcoplasmic reticulum (SR) of VSMCs and have been shown to activate VSMC BKCa channels to cause hyperpolar-ization, leading to a reduced open probability of L-type voltage-gated Ca~(2+) channels (VGCCs) and a decrease in cytosolic [Ca~(2+)] (21). Ca~(2+) spark frequency can be increased by activation of transient receptor protein (TRP) channels (4) and has been hypothesized to act as an intrinsic negative-feedback mechanism to regulate stretch-induced VSMC depolarization and myogenic tone (10). Although RyR activity can be directly modulated in VSMCs (12), endothelial cell (EC)-derived factors can also increase VSMC Ca~(2+) spark activity (4, 8, 18), supporting a role for the endothelium in regulating VSMC RyR. Both nitric oxide (NO) and carbon monoxide (CO), two endothelium-derived dilators that function similarly to H2S in many tissues, have been shown to modulate spark activity (20). Based on the previous description of VSMC BKca channel activation by Ca~(2+) sparks downstream of CO and NO and our observations of EC-dependent dilation by H2S, we hypothesized that H2S activates Ca~(2+) sparks in an EC-dependent manner to contribute to VSMC hyperpolarization and vasodilation.