Vol. 294, Issue 3, 963-968, September 2000

Influence of Purinoceptor Antagonism on Diadenosine Pentaphosphate-Induced Hypotension in Anesthetized Rats¹

Martin Steinmetz, Truc Van Le, Peter Hollah, Gert Gabriëls, Helge Hohage, Karl Heinz Rahn and Eberhard Schlatter

Medizinische Poliklinik, Experimentelle Nephrologie, Westfälische Wilhelms-Universität, Münster, Germany

Diadenosine polyphosphates (ApnA; n = 3-6) are potent vasoactive agents in isolated vessels. Information on effects of ApnA in vivo is still limited despite the fact that these compounds are starting to be used in humans. This study was designed to compare the effects of ApnA and their possible metabolites on blood pressure in vivo and to functionally identify purinoceptors involved in their action. All four ApnA and their degradation products induced a sustained drop of mean arterial blood pressure during i.v. infusion, which was fully reversible. The rank order of potency was Ap4A  Ap6A > Ap5A = Ap3A = ATP = ADP > AMP  adenosine, suggesting that the hypotensive effect is predominantly evoked by the original dinucleotides and not by their degradation products. The hypotensive effect of Ap5A was reduced by the P2X and P2Y₁ purinoceptor antagonist pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid, the A₁ purinoceptor antagonist 8-cyclopentyl-1,3-dipropylxanthine, and the A₂ purinoceptor antagonist 3,7-dimethyl-1-propargylxanthine. The hypertensive effect by the prototype P2X receptor agonist -methylene ATP was inhibited by pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid, too. Purinoceptor antagonists reduced the maximal effects of the agonists indicating a noncompetitive inhibition. In summary, the reported vasocontractile effect of ApnA seems to be limited to isolated preparations under resting tone conditions; however, the systemic cardiovascular effects of all four ApnA are hypotensive, also making them candidates for blood pressure reduction in humans. These effects are fast in onset and easily reversible. Activation of different purinoceptors in the vasculature (most probably P2Y₁ and A₂ receptors) contributes to the Ap5A-induced decrease of mean arterial blood pressure.