Abstract 637: Hydrogen Sulfide Acts on Endothelial Cells to Elicit Dilation.
Hydrogen sulfide (H2S), produced by the enzyme cystathionine-γ lyase (CSE), dilates arteries by hyperpolarizing and relaxing vascular smooth muscle cells (VSMC) and CSE knock-out causes hypertension and endothelial dysfunction showing the importance of this system. However, it is not clear if H2S-induced VSMC depolarization and relaxation is mediated by direct effects on VSMC or indirectly through actions on endothelial cells (EC). We reported previously that disrupting EC prevents H2S-induced vasodilation suggesting H2S might act directly on EC. Because inhibiting large-conductance Ca2+-activated K+ (BKCa) channels also inhibits H2S-induced dilation, we hypothesized that H2S activates EC BKCa channels to hyperpolarize EC and increase EC Ca2+ which stimulates release of a secondary hyperpolarizing factor. Small mesenteric arteries from male Sprague-Dawley rats were used for all experiments. We found that EC disruption prevented H2S-induced VSMC membrane potential (Em) hyperpolarization. Blocking EC BKCa channels with luminal application of the BKCa inhibitor, iberiotoxin (IbTx, 100 nM), also prevented NaHS-induced dilation and VSMC hyperpolarization but did not affect resting VSMC Em showing EC specific actions. Sharp electrode recordings in arteries cut open to expose EC demonstrated H2S-induced hyperpolarization of EC while Ca2+ imaging studies in fluor-4 loaded EC showed that H2S increases EC Ca2+ event frequency. Thus H2S can act directly on EC. Inhibiting the EC enzyme cytochrome P450 2C (Cyp2C) with sulfaphenazole also prevented VSMC depolarization and vasodilation. Finally, inhibiting TRPV4 channels to block the target of the Cyp2C product 11,12-EET inhibited NaHS-induced dilation. Combined with our previous report that CSE inhibition decreases BKCa currents in EC, these results suggest that H2S stimulates EC BKCa channels and activates Cyp2C upstream of VSMC hyperpolarization and vasodilation.
- © 2012 by American Heart Association, Inc.