Vasorelaxation elicited by endogenous and exogenous hydrogen sulfide in mouse mesenteric arteries

H₂S causes vasorelaxation however there is considerable heterogeneity in the reported pharmacological mechanism of this effect. This study examines the contribution of endogenously released H₂S in the regulation of vascular tone and the mechanism of H₂S-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 H₂S-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 H₂S donor, NaHS, elicited a full and biphasic vasorelaxation response in mesenteric arteries (EC₅₀ (1) 8.7 μM, EC₅₀ (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^-/HCO₃^- exchanger (P < 0.05). Further experiments showed that NaHS can significantly inhibit voltage-gated Ca²⁺ channel function (P < 0.05). The vasorelaxant effect of H₂S in small resistance-like arteries is complex, involving eNOS, K⁺ channels, Cl^-/HCO₃^- exchanger, and voltage-gated Ca²⁺ 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.