Vasorelaxant Effect of a New Hydrogen Sulfide-Nitric Oxide Conjugated Donor in Isolated Rat Aortic Rings through cGMP Pathway

Endothelium-dependent vasorelaxant injury leads to a lot of cardiovascular diseases. Both hydrogen sulfide (H(2)S) and nitric oxide (NO) are gasotransmitters, which play a critical role in regulating vascular tone. However, the interaction between H(2)S and NO in vasorelaxation is still unclear. ZYZ-803 was a novel H(2)S and NO conjugated donor developed by H(2)S-releasing moiety (S-propyl-L-cysteine (SPRC)) and NO-releasing moiety (furoxan). ZYZ-803 could time- and dose-dependently relax the sustained contraction induced by PE in rat aortic rings, with potencies of 1.5- to 100-fold greater than that of furoxan and SPRC. Inhibition of the generations of H(2)S and NO with respective inhibitors abolished the vasorelaxant effect of ZYZ-803. ZYZ-803 increased cGMP level and the activity of vasodilator stimulated phosphoprotein (VASP) in aortic rings, and those effects could be suppressed by the inhibitory generation of H(2)S and NO. Both the inhibitor of protein kinase G (KT5823) and the inhibitor of K(ATP) channel (glibenclamide) suppressed the vasorelaxant effect of ZYZ-803. Our results demonstrated that H(2)S and NO generation from ZYZ-803 cooperatively regulated vascular tone through cGMP pathway, which indicated that ZYZ-803 had therapeutic potential in cardiovascular diseases.