Adenosine deaminase inhibition enhances the inotropic response mediated by A₁ adenosine receptor in hyperthyroid guinea pig atrium

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• 作者：Adam Kemeny-Beke ; Anita Jakab ; Judit Zsuga ; Miklos Vecsernyes ; Denes Karsai ; Fanni Pasztor ; Maria Grenczer ; Andras Jozsef Szentmiklosi ; Andras Berta ; Rudolf Gesztelyi
• 关键词：Adenosine deaminase ; Pentostatin ; EHNA ; Thyroid hormones ; Atrium ; Heart ; Guinea pig
• 刊名：Pharmacological Research
• 出版年：2007
• 出版时间：August 2007
• 年：2007
• 卷：56
• 期：2
• 页码：124-131
• 全文大小：367 K

文摘

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 E_max (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 ± 0.07 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 A₁ 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.