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1 Department of Pharmacology, New York Medical College, Valhalla, NY, USA
2 Department of Pharmacology, Harbin Medical University, Harbin, China
* To whom correspondence should be addressed. E-mail: wenhui_wang{at}nymc.edu.
We used the patch-clamp technique to examine the effect of adenosine on ENaC activity in the rat cortical collecting duct (CCD). Application of cyclohexyladenosine (CHA), an A1 adenosine receptor agonist, inhibited the ENaC activity, defined by NPo, 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 CGS21680, an A2a 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 the stimulation of the A1 adenosine receptor. Inhibition of phospholipase C with U73122 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 phospholipase A2 inhibitor , AACOCF3. 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 MS-PPOH. Inhibition of CYP450 epoxygenase with MS-PPOH blocked the effect of CHA on ENaC. In contrast, CHA reduced the ENaC activity in the presence of indomethacin. This suggests that CYP-epoxygenase dependent metabolites of AA mediate the effect of adenosine. Since 11,12-epoxyeicosatrienoic acid (11,12-EET) inhibits ENaC activity in the CCD (26), the role of 11,12-EET in mediating the effect of adenosine on ENaC was examined. Addition of 11,12-EET inhibited the 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 A1 adenosine receptor in the CCD and that the effect of adenosine is mediated by 11,12-EET.
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