title: Vasorelaxant Effect of a New Hydrogen Sulfide-Nitric Oxide Conjugated Donor in Isolated Rat Aortic Rings through cGMP Pathway.
abstract: Endothelium-dependent vasorelaxant injury leads to a lot of cardiovascular diseases. Both hydrogen sulfide (H2S) and nitric oxide (NO) are gasotransmitters, which play a critical role in regulating vascular tone. However, the interaction between H2S and NO in vasorelaxation is still unclear. ZYZ-803 was a novel H2S and NO conjugated donor developed by H2S-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 H2S 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 H2S and NO. Both the inhibitor of protein kinase G (KT5823) and the inhibitor of KATP channel (glibenclamide) suppressed the vasorelaxant effect of ZYZ-803. Our results demonstrated that H2S and NO generation from ZYZ-803 cooperatively regulated vascular tone through cGMP pathway, which indicated that ZYZ-803 had therapeutic potential in cardiovascular diseases.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Qingxun
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Fenfen
authors.initials: F
authors.lastname: Ma
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China ; Department of Pharmacology, Loo Yong Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Yi Zhun
authors.initials: YZ
authors.lastname: Zhu
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002227:Carbazoles / Q000494:pharmacology; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006862:Hydrogen Sulfide / Q000378:metabolism*; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015290:Second Messenger Systems / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D002227:Carbazoles; D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010750:Phosphoproteins; D014665:Vasodilator Agents; D000098662:Vasodilator-Stimulated Phosphoprotein; C073601:KT 5823; D009569:Nitric Oxide; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP; D006862:Hydrogen Sulfide