Abstract
The extracellular cAMP-adenosine pathway is the cellular egress of cAMP followed by extracellular conversion of cAMP to adenosine by the sequential actions of ecto-phosphodiesterase and ecto-5′-nucleotidase. Although detailed studies in isolated organs, tissues, and cells provide evidence for an extracellular cAMP-adenosine pathway, whether this mechanism contributes significantly to adenosine production in vivo is unclear. 1,3-Dipropyl-8-p-sulfophenylxanthine is restricted to the extracellular compartment due to a negative charge at physiological pH and, at high concentrations (≥0.1 mM), blocks ecto-phosphodiesterase. Here, we show that administration of 1,3-dipropyl-8-p-sulfophenylxanthine at a dose that provided concentrations in plasma and urine of approximately 0.3 and 6 mM, respectively, inhibited urinary adenosine excretion. In Sprague-Dawley rats i.v., 1,3-dipropyl-8-p-sulfophenylxanthine (10 mg + 0.15 mg/min) significantly decreased by 48 and 39% the urinary excretion of adenosine (from 3.57 ± 0.38 to 1.87 ± 0.14 nmol/30 min; p = 0.0003) and the ratio of urinary adenosine to cAMP (from 0.93 ± 0.08 to 0.57 ± 0.06; p = 0.0044), respectively, without altering blood pressure, renal blood flow, or glomerular filtration rate. Although 1,3-dipropyl-8-p-sulfophenylxanthine transiently increased urine volume and sodium excretion, these effects subsided, yet adenosine excretion remained reduced. Thus, changes in systemic and renal hemodynamics and excretory function could not account for the effects of 1,3-dipropyl-8-p-sulfophenylxanthine on adenosine excretion. Additional experiments showed that 1,3-dipropyl-8-p-sulfophenylxanthine, as in Sprague-Dawley rats, significantly attenuated adenosine excretion and the ratio of urinary adenosine to cAMP in both Wistar-Kyoto rats and spontaneously hypertensive rats. We conclude that the extracellular cAMP-adenosine pathway significantly contributes to the in vivo production of adenosine.
Footnotes
-
This work was supported by the National Institutes of Health (Grant HL 69846).
-
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
-
doi:10.1124/jpet.106.112748.
-
ABBREVIATIONS: SHR, spontaneously hypertensive rat; WKY, Wistar-Kyoto; PE, polyethylene; MABP, mean arterial blood pressure; RBF, renal blood flow; DPSPX, 1,3-dipropyl-8-p-sulfophenylxanthine; GFR, glomerular filtration rate; HPLC, high-pressure liquid chromatography; ANOVA, analysis of variance; LSD, least significant difference test; IBMX, 3-isobutyl-1-methylxanthine.
- Received August 18, 2006.
- Accepted October 5, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|