Influence of purinoceptor antagonism on diadenosine pentaphosphate-induced hypotension in anesthetized rats.
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 > or = Ap6A > Ap5A = Ap3A = ATP = ADP > AMP > or = 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 P2Y(1) purinoceptor antagonist pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid, the A(1) purinoceptor antagonist 8-cyclopentyl-1,3-dipropylxanthine, and the A(2) purinoceptor antagonist 3, 7-dimethyl-1-propargylxanthine. The hypertensive effect by the prototype P2X receptor agonist alphabeta-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 P2Y(1) and A(2) receptors) contributes to the Ap5A-induced decrease of mean arterial blood pressure.
Steinmetz
M
M
Medizinische Poliklinik, Experimentelle Nephrologie, Westfälische Wilhelms-Universität, Münster, Germany.
van Le
T
T
Hollah
P
P
Gabriëls
G
G
Hohage
H
H
Rahn
K H
KH
Schlatter
E
E
D000818:Animals; D015226:Dinucleoside Phosphates / Q000494:pharmacology*; D007022:Hypotension / Q000503:physiopathology*; D008297:Male; D058915:Purinergic P1 Receptor Antagonists; D058919:Purinergic P2 Receptor Antagonists; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D058472:Receptors, Purinergic P2Y1; D013805:Theobromine / Q000031:analogs & derivatives / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology*; D014970:Xanthines / Q000494:pharmacology
D015226:Dinucleoside Phosphates; C546382:P2RY1 protein, human; D058915:Purinergic P1 Receptor Antagonists; D058919:Purinergic P2 Receptor Antagonists; D058472:Receptors, Purinergic P2Y1; D014665:Vasodilator Agents; D014970:Xanthines; C077792:pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid; C012275:P(1),P(5)-di(adenosine-5'-)pentaphosphate; D011732:Pyridoxal Phosphate; C057837:3,7-dimethyl-1-propargylxanthine; C051360:1,3-dipropyl-8-cyclopentylxanthine; D013805:Theobromine