title: Nucleoside monophosphorothioates as the new hydrogen sulfide precursors with unique properties.
abstract: 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.
authors: Department of Pathophysiology, Medical University, Lublin, Poland. Electronic address: jerzy.beltowski@umlub.pl.
authors: Jerzy
authors: J
authors: Bełtowski
authors: Department of Biochemistry and Biotechnology, Poznań University of Life Sciences, Poznań, Poland.
authors: Andrzej
authors: A
authors: Guranowski
authors: Department of Neurology, Medical University, Lublin, Poland.
authors: Anna
authors: A
authors: Jamroz-Wiśniewska
authors: Department of Pathomorphology, Medical University, Lublin, Poland.
authors: Agnieszka
authors: A
authors: Korolczuk
authors: Department of Vascular Surgery, Medical University, Lublin, Poland.
authors: Andrzej
authors: A
authors: Wojtak
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000241:Adenosine / Q000378:metabolism; D000249:Adenosine Monophosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006157:Guanosine Monophosphate / Q000494:pharmacology*; D006862:Hydrogen Sulfide / Q000378:metabolism*; D066298:In Vitro Techniques; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D008297:Male; D058911:Purinergic P2X Receptor Agonists / Q000494:pharmacology; D017208:Rats, Wistar; D013873:Thionucleotides / Q000494:pharmacology*
chemical_list: D058911:Purinergic P2X Receptor Agonists; D013873:Thionucleotides; C014308:adenosine 5'-phosphorothioate; D000249:Adenosine Monophosphate; C033901:3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate; C066524:guanosine 5'-monophosphorothioate; D006157:Guanosine Monophosphate; D000255:Adenosine Triphosphate; D055372:AMP-Activated Protein Kinases; D000241:Adenosine; D006862:Hydrogen Sulfide
keywords: A-438079 (PubChem CID: 11673921); A-769662 (PubChem CID: 54708532); AMP-stimulated protein kinase; Adenosine; Adenosine monophosphorothioate (PubChem CID: 21714625), Guanosine monophosphorothioate (PubChem CID: 11122713); BzATP (PubChem CID: 115205); Compound C (PubChem CID: 11524144); Hint proteins; Hydrogen sulfide; Hydrogen sulfide (PubChem CID: 402); Nucleoside phosphorothioates; P2X(7) receptor; d,l-Propargylglycine (PubChem CID: 95575); l-Cysteine (PubChem CID: 5862)