LAUSR

H 2 S causes vasorelaxation however there is considerable heterogeneity in the reported pharmacological mechanism of this effect. This study examines the contribution of endogenously released H 2 S in the regulation of vascular tone and the mechanism of H 2 S-induced vasorelaxation in small resistance-like arteries. Mesenteric arteries from C57 and eNOS −/− mice were mounted in myographs to record isometric force. Vasorelaxation responses to NaHS were examined in the presence of various inhibitors of vasorelaxation pathways. Expression and activity of the H 2 S-producing enzyme, cystathionine-γ-lyase (CSE), were also examined. CSE was expressed in vascular smooth muscle and perivascular adipose cells from mouse mesenteric artery. The substrate for CSE, l -cysteine, caused a modest vasorelaxation (35%) in arteries from C57 mice and poor vasorelaxation (10%) in arteries from eNOS −/− mice that was sensitive to the CSE inhibitor dl -propargylglycine. The fast H 2 S donor, NaHS, elicited a full and biphasic vasorelaxation response in mesenteric arteries (EC 50 (1) 8.7 μM, EC 50 (2) 0.6 mM), which was significantly inhibited in eNOS −/− vessels ( P < 0.05), unaffected by endothelial removal, or blockers at any point in the NO via soluble guanylate cyclase and cGMP (NO-sGC-cGMP) vasorelaxation pathway. Vasorelaxation to NaHS was significantly inhibited by blocking K + channels of the K Ca and K V subtypes and the Cl − /HCO 3 − exchanger ( P < 0.05). Further experiments showed that NaHS can significantly inhibit voltage-gated Ca 2+ channel function ( P < 0.05). The vasorelaxant effect of H 2 S in small resistance-like arteries is complex, involving eNOS, K + channels, Cl − /HCO 3 − exchanger, and voltage-gated Ca 2+ channels. CSE is present in the smooth muscle and periadventitial adipose tissue of these resistance-like vessels and can be activated to cause modest vasorelaxation under these in vitro conditions.