期刊
PHARMACOLOGICAL RESEARCH
卷 56, 期 2, 页码 124-131出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.phrs.2007.04.017
关键词
adenosine deaminase; pentostatin; EHNA; thyroid hormones; atrium; heart; guinea pig
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 A, adenosine receptors in hyperthyroidism. The inotropic response to N-6-cyclopentyladenosine (CPA), a selective A, 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 Em(ax) (mean +/- S.E.M.) from 83.8 +/- 1.2% to 93.4 +/- 1.2%, while DCF significantly decreased the log EC50 from -7.5 +/- 0.07 to -7.83 +/- 10.07 in hyperthyroid samples. Conversely, EHNA also diminished the log EC50 (from -7.5 +/- 0.07 to -7.65 +/- 0.07) and DCF also raised the E-max (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, 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 A I 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 A, adenosine receptor signaling in the hyperthyroid guinea pig atrium. (c) 2007 Elsevier Ltd. All rights reserved.
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