title: Adenosine deaminase inhibition enhances the inotropic response mediated by A1 adenosine receptor in hyperthyroid guinea pig atrium.
abstract: The aim of the present study was to test the hypothesis that inhibition of adenosine deaminase (ADA) enhances the efficiency of signal-transduction of myocardial A1 adenosine receptors in hyperthyroidism. The inotropic response to N6-cyclopentyladenosine (CPA), a selective A1 adenosine receptor agonist resistant to ADA, was investigated in the absence or presence of erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), an ADA and cGMP-stimulated 3',5'-cyclic nucleotide phosphodiesterase (PDE2) inhibitor, or of pentostatin (2'-deoxycoformycin; DCF), an exclusive ADA inhibitor, in left atria isolated from eu- or hyperthyroid guinea pigs. Both ADA inhibitors enhanced the effect of CPA only in hyperthyroid atria. EHNA significantly increased the Emax (mean+/-S.E.M.) from 83.8+/-1.2% to 93.4+/-1.2%, while DCF significantly decreased the logEC50 from -7.5+/-0.07 to -7.83+/-0.07 in hyperthyroid samples. Conversely, EHNA also diminished the logEC50 (from -7.5+/-0.07 to -7.65+/-0.07) and DCF also raised the Emax (from 83.8+/-1.2% to 85.7+/-2%) in hyperthyroidism, but these changes were not significant. In conclusion, ADA inhibition moderately but significantly enhanced the efficiency of A(1) adenosine receptor signaling pathway in the hyperthyroid guinea pig atrium. This suggests that elevated intracellular adenosine level caused by ADA inhibition may improve the suppressed responsiveness to A1 adenosine receptor agonists associated with the hyperthyroid state. Alternatively or in addition, the role of decreased concentration of adenosine degradation products cannot be excluded. Furthermore, in the case of EHNA, inhibition of PDE2 also appears to contribute to the enhanced A1 adenosine receptor signaling in the hyperthyroid guinea pig atrium.
authors.affiliation: Department of Ophthalmology, University of Debrecen, PO Box 30, H-4012 Debrecen, Hungary.
authors.forename: Adam
authors.initials: A
authors.lastname: Kemeny-Beke
authors.forename: Anita
authors.initials: A
authors.lastname: Jakab
authors.forename: Judit
authors.initials: J
authors.lastname: Zsuga
authors.forename: Miklos
authors.initials: M
authors.lastname: Vecsernyes
authors.forename: Denes
authors.initials: D
authors.lastname: Karsai
authors.forename: Fanni
authors.initials: F
authors.lastname: Pasztor
authors.forename: Maria
authors.initials: M
authors.lastname: Grenczer
authors.forename: Andras Jozsef
authors.initials: AJ
authors.lastname: Szentmiklosi
authors.forename: Andras
authors.initials: A
authors.lastname: Berta
authors.forename: Rudolf
authors.initials: R
authors.lastname: Gesztelyi
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D058907:Adenosine A1 Receptor Agonists; D000243:Adenosine Deaminase / Q000378:metabolism; D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D001593:Benzyl Compounds / Q000494:pharmacology; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism; D006980:Hyperthyroidism / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology; D007288:Inosine / Q000378:metabolism; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D015649:Pentostatin / Q000494:pharmacology* / Q000627:therapeutic use; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013974:Thyroxine
chemical_list: D058907:Adenosine A1 Receptor Agonists; D058892:Adenosine Deaminase Inhibitors; D001593:Benzyl Compounds; D004791:Enzyme Inhibitors; D010726:Phosphodiesterase Inhibitors; D043682:Receptor, Adenosine A1; C509055:erythro-(3-nonyl-p-aminobenzyl-adenine); D015649:Pentostatin; C048599:N(6)-cyclopentyladenosine; D007288:Inosine; D010727:Phosphoric Diester Hydrolases; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; D000243:Adenosine Deaminase; D000225:Adenine; D000241:Adenosine; D013974:Thyroxine