Abstract
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 αβ-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.
Footnotes
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Send reprint requests to: Prof. Dr. Eberhard Schlatter, Medizinische Poliklinik, Experimentelle Nephrologie, Westfälische Wilhelms-Universität, Domagkstrasse 3a, 48149 Münster, Germany. E-mail: eberhard.schlatter{at}uni-muenster.de
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↵1 This study was supported by a grant from the Center for Interdisciplinary Clinical Research (IZKF, project A1) at the Medical Faculty of the University of Münster (BMBF 01 KS 9604/0). A part of this work was presented at the Congress of Nephrology, Erlangen, Germany, 1998, and is published in abstract form (Schlatter et al., 1998).
- Abbreviations:
- ApnA
- diadenosine polyphosphates
- PPADS
- pyridoxal-phosphate-6-azophenyl-2′,4′-disulfonic acid
- DMPX
- 3,7-dimethyl-1-propargylxanthine
- DPCPX
- 8-cyclopentyl-1,3-dipropylxanthine
- MABP
- mean arterial blood pressure
- HR
- heart rate
- BPM
- beats per minute
- Ap3A
- P1,P3-diadenosine triphosphate
- Ap4A
- P1,P4-diadenosine tetraphosphate
- Ap5A
- P1,P5-diadenosine pentaphosphate
- Ap6A
- P1,P6-diadenosine hexaphosphate
- Received December 28, 1999.
- Accepted May 26, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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