Does conversion of ATP to adenosine terminate ATP-stimulated vasopressin release from hypothalamo-neurohypophyseal explants?

ATP stimulates vasopressin (VP) release from explants of the hypothalamo-neurohypophyseal system (HNS), but the response is not sustained for the duration of exposure to ATP. Since adenosine, a metabolite of ATP, inhibits VP release from neurohypophysial terminals and adenosine receptors (AR) are expressed in supraoptic nucleus (SON) neurons, we postulated that conversion of ATP to adenosine contributed to termination of ATP-stimulated VP release from HNS explants. This was tested using a non-selective AR antagonist, 5-amino-9-chloro-2-(2-furyl)-1, 2, 4-triazolo [1, 5-c] quinazoline (CGS-15943). CGS-15943 did not affect basal VP release and did not alter the initial response to ATP. A selective A1R antagonist, 8-cyclopentyl-1, 3-dipropylxanthine (DPCPX), increased basal VP release at 1 microM, without altering the response to ATP. However, at a higher concentration of DPCPX (10 microM), VP release was enhanced by ATP for an extended period of time. Inhibition of the enzymatic conversion of ATP to adenosine using a combination of a potent ecto-5'-nucleotidase inhibitor, alpha,beta-methylene adenosine 5'-diphosphate (AMP-CP), and a competitive substrate for ecto-5'-nucleotidase (guanosine monophosphate, GMP) did not affect basal VP release. Enzymatic inhibition did slightly prolong the response to ATP, but it was not sustained for the duration of exposure to ATP. We conclude that an endogenous inhibitory influence of adenosine decreases basal VP release from HNS explants and that conversion of exogenously applied ATP to adenosine contributes to termination of ATP-induced stimulation of VP release, but additional mechanisms such as receptor desensitization also limit the response to extended exposure to ATP.