Document Detail

Adenosine inhibits ENaC via cytochrome P-450 epoxygenase-dependent metabolites of arachidonic acid.
MedLine Citation:
PMID:  16234312     Owner:  NLM     Status:  MEDLINE    
We used the patch-clamp technique to examine the effect of adenosine on epithelial sodium channel (ENaC) activity in rat cortical collecting duct (CCD). Application of adenosine inhibits ENaC activity, and the effect of adenosine was mimicked by cyclohexyladenosine (CHA), an A(1) adenosine-receptor agonist that reduced channel activity from 1.32 to 0.64. The inhibitory effect of CHA on ENaC was mimicked by cyclopentyladenosine (CPA), which reduced channel activity from 1.1 to 0.55. In contrast, application of CGS-21680, an A(2a) adenosine-receptor agonist, had no effect on ENaC and increased channel activity from 0.96 to 1.22. This suggests that the inhibitory effect of adenosine analogs resulted from stimulation of the A(1) adenosine receptor. Inhibition of PLC with U-73122 failed to abolish the effect of CHA on ENaC. In contrast, the inhibitory effect of CHA on ENaC was absent in the presence of the PLA(2) inhibitor arachidonyl trifluoromethyl ketone (AACOCF(3)). This suggests a role of arachidonic acid (AA) in mediating the effect of adenosine on ENaC. To determine the metabolic pathway of AA responsible for the effect of adenosine, we examined the effect of CHA in the presence of indomethacin or N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH). Inhibition of cytochrome P-450 (CYP) epoxygenase with MS-PPOH blocked the effect of CHA on ENaC. In contrast, CHA reduced ENaC activity in the presence of indomethacin. This suggests that CYP epoxygenase-dependent metabolites of AA mediate the effect of adenosine. Because 11,12-epoxyeicosatrienoic acid (11,12-EET) inhibits ENaC activity in the CCD (Wei Y, Lin DH, Kemp R, Yaddanapudi GSS, Nasjletti A, Falck JR, and Wang WH. J Gen Physiol 124: 719-727, 2004), we examined the role of 11,12-EET in mediating the effect of adenosine on ENaC. Addition of 11,12-EET inhibited ENaC channels in the CCD in which adenosine-induced inhibition was blocked by AACOCF3. We conclude that adenosine inhibits ENaC activity by stimulation of the A(1) adenosine receptor in the CCD and that the effect of adenosine is mediated by 11,12-EET.
Yuan Wei; Peng Sun; Zhijian Wang; Baofeng Yang; Mairead A Carroll; Wen-Hui Wang
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2005-10-18
Journal Detail:
Title:  American journal of physiology. Renal physiology     Volume:  290     ISSN:  1931-857X     ISO Abbreviation:  Am. J. Physiol. Renal Physiol.     Publication Date:  2006 May 
Date Detail:
Created Date:  2006-04-07     Completed Date:  2006-05-22     Revised Date:  2011-04-28    
Medline Journal Info:
Nlm Unique ID:  100901990     Medline TA:  Am J Physiol Renal Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  F1163-8     Citation Subset:  IM    
Dept. of Pharmacology, New York Medical College, Valhalla, NY 10595, USA.
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MeSH Terms
Adenosine / metabolism,  physiology*
Arachidonic Acid / metabolism*
Cytochrome P-450 Enzyme System / metabolism*
Epithelial Sodium Channel
Kidney Tubules, Collecting / physiology
Oxygenases / metabolism*
Patch-Clamp Techniques
Rats, Sprague-Dawley
Receptor, Adenosine A1 / drug effects,  physiology
Sodium Channels / physiology*
Grant Support
Reg. No./Substance:
0/Epithelial Sodium Channel; 0/Receptor, Adenosine A1; 0/Sodium Channels; 506-32-1/Arachidonic Acid; 58-61-7/Adenosine; 9035-51-2/Cytochrome P-450 Enzyme System; EC 1.13.-/Oxygenases; EC epoxygenase

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