Pivotal role of phosphate chain length in vasoconstrictor versus vasodilator actions of adenine dinucleotides in rat mesenteric arteries.

Ralevic, Vera; Hoyle, Charles H.V.; Burnstock, Geoffrey

doi:10.1113/jphysiol.1995.sp020615

Cited by 96 publications

(85 citation statements)

References 27 publications

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“…First, our experiments revealed that AP4 is the most potent endogenous vasoactive purinergic compound currently known. Firstly, the synthetic substance ␣,␤-meATP 19,20 has been regarded as the most potent vasoconstrictive purinergic agonist. In the present experiments, AP4 exceeded the vasoconstrictive potency of ␣,␤-meATP in vitro significantly.…”

Section: Discussionmentioning

confidence: 99%

Adenosine 5′-Tetraphosphate Is a Highly Potent Purinergic Endothelium-Derived Vasoconstrictor

Tölle

Jankowski

Schuchardt

et al. 2008

Circulation Research

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Abstract-Besides serving as a mechanical barrier, the endothelium has important regulatory functions. The discovery of nitric oxide revolutionized our understanding of vasoregulation. In contrast, the identity of endothelium-derived vasoconstrictive factors still remains uncertain. The supernatant from mechanically stimulated human microvascular endothelial cells elicited a potent vasoconstrictive response in the isolated perfused rat kidney. Whereas a nonselective purinoceptor blocker blocked this vasoactivity most potently, the inhibition of the endothelin receptor by BQ123 weakly affected that vasoconstrictive response. As a compound responsible for that vasoconstrictive effect, we have isolated from HMECs and identified the mononucleotide adenosine 5Ј-tetraphosphate (AP4). This nucleotide proved to be the most potent vasoactive purinergic mediator identified to date, exerting the vasoconstriction predominantly through activation of the P2X1 receptor. The intraarterial application of AP4 in a Wistar-Kyoto rat induced a strong increase of the mean arterial pressure. The plasma concentration of AP4 is in the nanomolar range, which, in vivo, induces a significant change in the mean arterial pressure. To our knowledge, AP4, which exerts vasoactive effects, is the most potent endogenous mononucleotide identified to date in mammals. The effects of AP4, the plasma concentration of AP4, and its release suggest that this compound functions as an important vasoregulator.

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Section: Discussionmentioning

confidence: 99%

Adenosine 5′-Tetraphosphate Is a Highly Potent Purinergic Endothelium-Derived Vasoconstrictor

Tölle

Jankowski

Schuchardt

et al. 2008

Circulation Research

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“…In the vas deferens and urinary bladder their actions are through a P2X-purinoceptor (MacKenzie et al, 1988;Hoyle et al, 1989;; in bovine adrenal gland endothelial and chromaffin cells as well as in the rat mesenteric vascular bed the effects of Ap4A and Ap5A are mediated by P2U, P2x and P2y-purinoceptors, respectively (Pintor et al, 1991;Castro et al, 1994;Ralevic et Drinoce.tor d-a --al., 1994). The recent discovery of the P2D-purinoceptor (Pintor et al, 1993a), highly specific for diadenosine polyphosphates in synaptic terminals, reinforced the theory of the existence of different purinoceptors for nucleotides and dinucleotides (Stone & Perkins, 1981;Hoyle, 1990).…”

Section: Introductionmentioning

confidence: 99%

A novel receptor for diadenosine polyphosphates coupled to calcium increase in rat midbrain synaptosomes

Pintor

Miras‐Portugal

1995

British J Pharmacology

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1 Diadenosine polyphosphates, Ap4A and Ap5A, as well as ATP, c,fl-MeATP and ADP-P-S, were able to elicit variable intrasynaptosomal Ca21 increases in rat midbrain synaptic terminals. The origin of the Ca2+ increment was the extrasynaptosomal space since the elimination of extracellular Ca2+ abolished the effect of all the agonists. 2 The P2-purinoceptor antagonist, suramin, did not affect the Ca2+-increase evoked by diadenosine polyphosphates but dramatically blocked the Ca2+ entry induced by ATP and its synthetic analogues. 3 The actions of Ap5A and ATP on the intrasynaptosomal Ca21 increase did not cross-desensitize. 4 Concentration-response studies for diadenosine polyphosphates showed pD2 values of 54.5 ± 4.2 uM and 55.6 ± 3.8 yM for Ap4A and Ap5A, respectively. 5 The entry of calcium induced by diadenosine polyphosphates could be separated into two components. The first represented a selective voltage-independent Ca2+ entry; the second, a sustained phase which was voltage-dependent. 6 Studies on the voltage-dependent Ca2 +-channels involved in the effects of the diadenosine polyphosphates, demonstrated that o-conotoxin G-VI-A inhibited the sustained Ca2+-entry, suggesting the participation of an N-type Ca2+-channel. This toxin was unable to abolish the initial cation entry induced by Ap4A or ApNA. co-Agatoxin IV-A, tetrodotoxin, or nifedipine did not inhibit the effects of the diadenosine polyphosphates. 7 The effect of ATP on Ca2+-entry was abolished by nifedipine and co-conotoxin G-VI-A, suggesting the participation of L-and N-type Ca2"-channels in the response to ATP.8 These data suggest that Ap4A, Ap5A and ATP activate the same intracellular Ca21 signal through different receptors and different mechanisms. Ap4A and Ap5A induce a more selective Ca2+-entry in a voltage-independent process. This is the first time that a selective action of diadenosine polyphosphate through receptors other than PI and P2-purinoceptors has been described.

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“…The rank order of contractile potency of ApnA in hMRA is comparable with rat MRA (Steinmetz eat al., 2000b) and principally also with the perfused rat mesenteric artery (Ralevic et al, 1995), where a pivotal role of the phosphate chain length for the pharmacological potency of the ApnA was postulated. These observations are also compatible with Gabriels et al (2000), who found stronger vasoconstrictions by Ap5A than by Ap3A in interlobar arteries of hydronephrotic rat kidneys.…”

Section: Discussionmentioning

confidence: 99%

“…Purinergic vasodilation was shown to be mediated via P2Y purinoceptors (Ralevic et al, 1995). Ap5A-induced vasorelaxation in rat MRA was inhibited by P2Y receptor blockade (Steinmetz et al, 2000a).…”

Section: Discussionmentioning

confidence: 99%

“…In rat mesenteric resistance arteries ApnA-induced effects are independent of the endothelium or of perivascular innervation (Steinmetz et al, 2000b). The potency of ApnA-induced vasoactivity in the isolated vessel preparations of the rat is dependent on the chain length of the ApnA (n ϭ 3-6) with an optimum at Ap5A (followed by Ap6A, Ap4A, and Ap3A) (Ralevic et al, 1995;van der Giet et al, 1997;Steinmetz et al, 2000b). However, in anesthetized rats, systemically applied (i.e., intravenously infused) ApnA induced a sustained hypotension; herein, Ap4A had the highest potency (followed by Ap6A, Ap5A, and Ap3A), and Ap4A was also used for interrupting hypertensive episodes during anesthesia in humans (Kikuta et al, 1999), which emphasizes the growing importance of these purinergic physiological substances for clinical application.…”

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confidence: 99%

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Vasoactivity of Diadenosine Polyphosphates in Human Small Mesenteric Resistance Arteries

Steinmetz¹,

Janssen²,

Pelster³

et al. 2002

J Pharmacol Exp Ther

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Diadenosine polyphosphates (ApnA) (n ϭ 3-6) induced vasoconstrictions in isolated human mesenteric resistance arteries (hMRAs) mounted in a microvessel myograph (rank order of potency: Ap5A Ͼ Ap6A Ͼ Ap4A Ͼ Ap3A). The contractile effects of ApnA in hMRA were similar to their effects in rat MRA investigated previously. ATP, ADP, AMP, and adenosine had less contractile potency than ApnA, suggesting that the observed effects were not induced by the degradation products of ApnA. Ap4A-and Ap5A-induced vasoconstriction was inhibited by pyridoxalphosphate-6-azophenyl-2Ј,4Ј-disulfonic acid (PPADS) (P2X purinoceptor antagonist) but not by ADP3Ј5Ј (P2Y purinoceptor antagonist). Thus, this purinergic vasoconstriction of hMRA seems to be P2X but not P2Y purinoceptormediated. In precontracted hMRA all ApnA caused vasorelaxations but (in contrast to rat MRA) the potencies of the ApnA did not differ significantly from each other. The ApnA degradation products had less vasorelaxing potency than ApnA, demonstrating that the vasorelaxations can be ascribed to the ApnA themselves. Ap5A-induced vasorelaxation of hMRA could neither be inhibited with ADP3Ј5Ј nor with PPADS, which reveals a decisive difference to the rat MRA where the inhibitory profile demonstrated the importance of the P2Y purinoceptor for Ap5A-induced vasorelaxation. However, Ap4A-induced vasorelaxation in hMRA could be inhibited by ADP3Ј5Ј. These findings show that Ap4A-induced vasorelaxation in hMRA is due to P2Y purinoceptor activation, that Ap5A evokes vasorelaxation in hMRA via another mechanism than Ap4A, and that data derived from the animal model cannot be simply transferred to human conditions.

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Pivotal role of phosphate chain length in vasoconstrictor versus vasodilator actions of adenine dinucleotides in rat mesenteric arteries.

Cited by 96 publications

References 27 publications

Adenosine 5′-Tetraphosphate Is a Highly Potent Purinergic Endothelium-Derived Vasoconstrictor

Adenosine 5′-Tetraphosphate Is a Highly Potent Purinergic Endothelium-Derived Vasoconstrictor

A novel receptor for diadenosine polyphosphates coupled to calcium increase in rat midbrain synaptosomes

Vasoactivity of Diadenosine Polyphosphates in Human Small Mesenteric Resistance Arteries

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