PROPENTOFYLLINE AND OTHER ADENOSINE TRANSPORT INHIBITORS INCREASE THEEFFLUX OF ADENOSINE FOLLOWING ELECTRICAL OR METABOLIC STIMULATION OF RAT HIPPOCAMPAL SLICES

Propentofylline is a novel neuroprotective agent that has been shown t o act as an adenosine transport inhibitor as well as an adenosine rece ptor antagonist. In the present series of experiments we have compared the effects of propentofylline with those of known adenosine transpor t inhibitors and receptor antagonists on the formation of adenosine in rat hippocampal slices. The ATP stores were labeled by incubating the slices with [H-3]-adenine. The total H-3 overflow and the overflow of endogenous and H-3-labeled adenosine, inosine, and hypoxanthine were measured. Adenosine release, secondary to ATP breakdown, was induced b oth by hypoxia/hypoglycemia and by electrical field stimulation. Prope ntofylline (20-500 mu M) increased the release of endogenous and radio labeled adenosine, without increasing the total release of purines. Th us, the drug altered the pattern of released purines, i.e., increasing adenosine and decreasing inosine and hypoxanthine. This pattern, whic h was observed when purine release was induced both by electrical fiel d stimulation and, by hypoxia/hypoglycemia, was shared by the nucleosi de transport inhibitor dipyridamole (1 mu M) and by mioflazine (1 mu M ) and nitrobenzylthioinosine (1 mu M). By contrast, other xanthines, i ncluding theophylline (100 mu M) and 8-cyclopentyltheophylline (10 mu M), enprofylline (100 mu M), or torbafylline (300 mu M), if anything, increased the total release of purines without alterations of the patt ern of release. These results indicate that nucleoside transport inhib itors can decrease the release of purines from cells and at the same t ime increase the concentration of extracellular adenosine, possibly by preventing its uptake and subsequent metabolism. This change in purin e metabolism may be beneficial with regard to cell damage after ischem ia. The results also indicate that propentofylline behaves in such a p otentially beneficial manner.