guanosine-monophosphate and adenosine-5--phosphorothioate

Hydrogen sulfide (H2S) is synthesized in perivascular adipose tissue (PVAT) and induces vasorelaxation. We examined whether the sulfur-containing AMP and GMP analogs AMPS and GMPS can serve as the H2S donors in PVAT. H2S production by isolated rat periaortic adipose tissue (PAT) was measured with a polarographic sensor. In addition, phenylephrine-induced contractility of aortic rings with (+) or without (-) PAT was examined. Isolated PAT produced H2S from AMPS or GMPS in the presence of the P2X7 receptor agonist BzATP. Phenylephrine-induced contractility of PAT(+) rings was lower than of PAT(-) rings. AMPS or GMPS had no effect on the contractility of PAT(-) rings, but used together with BzATP reduced the contractility of PAT(+) rings when endogenous H2S production was inhibited with propargylglycine. A high-fat diet reduced endogenous H2S production by PAT. Interestingly, AMPS and GMPS were converted to H2S by PAT of obese rats, and reduced contractility of PAT(+) aortic rings isolated from these animals even in the absence of BzATP. We conclude that (i) AMPS and GMPS can be hydrolyzed to H2S by PAT when P2X7 receptors are activated, (ii) a high-fat diet impairs endogenous H2S production by PAT, (iii) AMPS and GMPS restore the anticontractile effects of PAT in obese animals without P2X7 stimulation.

Topics: Adenosine Monophosphate; Adipose Tissue; Animals; Aorta; Aorta, Abdominal; Aorta, Thoracic; Guanosine Monophosphate; Hydrogen Sulfide; In Vitro Techniques; Male; Muscle Contraction; Muscle, Smooth, Vascular; Obesity; Rats, Wistar; Thionucleotides; Vasodilation

Hydrogen sulfide (H2S) is the gasotransmitter enzymatically synthesized in mammalian tissues from l-cysteine. H2S donors are considered as the potential drugs for the treatment of cardiovascular, neurological and inflammatory diseases. Recently, it has been demonstrated that synthetic nucleotide analogs, adenosine- and guanosine 5'-monophosphorothioates (AMPS and GMPS) can be converted to H2S and AMP or GMP, respectively, by purified histidine triad nucleotide-binding (Hint) proteins. We examined if AMPS and GMPS can be used as the H2S donors in intact biological systems. H2S production by isolated rat kidney glomeruli was measured by the specific polarographic sensor. H2S production was detected when glomeruli were incubated with AMPS or GMPS and ionotropic purinergic P2X7 receptor/channel agonist, BzATP. More H2S was generated from GMPS than from equimolar amount of AMPS. Nucleoside phosphorothioates together with BzATP relaxed angiotensin II-preconstricted glomeruli. In addition, infusion of AMPS or GMPS together with BzATP into the renal artery increased filtration fraction and glomerular filtration rate but had no effect on renal vascular resistance or renal blood flow. AMPS but not GMPS was converted to adenosine by isolated glomeruli, however, adenosine was not involved in AMPS-induced H2S synthesis because neither adenosine nor specific adenosine receptor agonists had any effect on H2S production. AMPS, but not GMPS, increased phosphorylation level of AMP-stimulated protein kinase (AMPK), but AMPK inhibitor, compound C, had no effect on AMPS-induced H2S production. In conclusion, nucleoside phosphorothioates are converted to H2S which relaxes isolated kidney glomeruli in vitro and increases glomerular filtration rate in vivo. AMPS and GMPS can be used as the H2S donors in experimental studies and possibly also as the H2S-releasing drugs.

Topics: Adenosine; Adenosine Monophosphate; Adenosine Triphosphate; AMP-Activated Protein Kinases; Animals; Glomerular Filtration Rate; Guanosine Monophosphate; Hydrogen Sulfide; In Vitro Techniques; Kidney Glomerulus; Male; Purinergic P2X Receptor Agonists; Rats, Wistar; Thionucleotides