Abstract

The relaxant properties of the putative selective P2Y agonist adenosine 5'-(2-fluorodiphosphate) (ADP-beta-F) and its structural analog adenosine 5'-(2-thiodiphosphate) have been investigated in the rabbit precontracted jugular vein preparation. In tissues with intact endothelium, ADP-beta-F produced a multiphasic agonist concentration/effect curve made up of two vasorelaxant components which were kinetically and pharmacologically distinct. The higher potency phase (p[A50] 5.58 +/- 0.13), characterized by slow, tonic responses, was retained after endothelial denudation and blocked by the selective P1 purinoceptor antagonist 8-sulphophenyltheophylline. The lower potency phase (p[A50] 3.98 +/- 0.07), characterized by fast, phasic responses, was abolished by endothelial denudation and is presumed to be mediated at P2Y purinoceptors. By contrast, the agonist concentration/effect curve to adenosine 5'-(2-dithiophosphate) in endothelium-intact tissues appear monophasic and was unaffected by 8-sulphophenyltheophylline (p[A50] 6.86 +/- 0.12), although endothelial denudation revealed a secondary P1-induced relaxant component (p[A50] 5.73 +/- 0.20). This study demonstrates that in the rabbit jugular vein, relaxant responses to ADP-beta-F are mediated primarily by activation of P1 purinoceptors, and it is, therefore, invalid to regard ADP-beta-F as a selective probe for P2Y purinoceptors, whereas adenosine 5'-(2-thiodiphosphate) does show some selectivity for this receptor.