S5-5 Nucleoside monophosphorothioates as the H2S donors in perivascular adipose tissue

Abstract

Adenosine and guanosine 5′-monophosphorothioates (AMPS and GMPS) are synthetic nucleotide analogs with one oxygen atom replaced by sulfur. We have demonstrated that these nucleoside monophosphorothioates (NMPs) are transported to the cell through purinergic receptor/channel P2X 7 and are hydrolyzed to H 2 S by intracellular Hint proteins. Herein we examined if NMPs can serve as the H 2 S donors in vascular wall. H 2 S production by isolated tunica media of the rat aorta and periaortic adipose tissue (PAT) was measured in vitro by the polarographic sensor. In addition, effect of NMPs on isometric tension of rat aortic rings with or without PAT was examined. H 2 S production from NMPs was observed in PAT only in the presence of P2X 7 agonist, BzATP, and was inhibited by P2X 7 antagonist, A-438079. Aortic media did not convert AMPS or GMPS to H 2 S. NMPs together with BzATP relaxed phenylephrine-preconstricted aortic rings with intact PAT but not rings with removed PAT. Effect of NMPs on vascular contractility was abolished by A-438079, H 2 S scavenger, bismuth subsalicylate, and K ATP channel antagonist, glibenclamide. NMPs relaxed PAT + aortic rings isolated from rats fed high-fat diet for 3 months even in the absence of BzATP and this effect was abolished by A-438079. The expression of P2X 7 in PAT was higher in obese than in control rats. AMPS and GMPS are converted to H 2 S in perivascular adipose tissue and induce H 2 S-dependent vasorelaxation. These nucleoside monophosphorothioates may be used as vasodilators particularly effective in obesity/metabolic syndrome.