Effects of Diadenosine Polyphosphates on Systemic and Regional Hemodynamics in Anesthetized Rats

Khattab, Mahmoud M.; Hohage, Helge; Hollah, Peter; Rahn, K. H.; Schlatter, Eberhard

doi:10.1159/000025842

Cited by 16 publications

(8 citation statements)

References 22 publications

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“…In anesthetized dogs and pigs, Ap4A caused a decrease in mean arterial pressure [12,13] which we demonstrated recently also for Ap4A, Ap5A and Ap6A [14]. Diadenosine polyphosphates induce negative chronotropic and inotropic responses in guineapig, canine, and human cardiac preparations [1,6,12].…”

Section: Introductionmentioning

confidence: 75%

“…The vascular tone in several organs is influenced by diadenosine polyphosphates. In vitro, Ap5A and Ap6A produced transient concentration-dependent contractions of the human umbilical artery [3]; all naturally occurring diadenosine polyphosphates increased the renal vascular tone in anesthetized rats [2,5,14]. Ap3A mediated endothelium-dependent vasodilation in the rat mesenteric artery [15] and endotheliumindependent vasodilation in the rabbit mesenteric artery [16].…”

Section: Introductionmentioning

confidence: 97%

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Effects of Diadenosine Polyphosphates on the Intracellular Ca<sup>2+</sup> Concentration in Endothelial Cells

Stachon

Stegemann²,

Hohage³

et al. 1998

Cell Physiol Biochem

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Diadenosine polyphosphates have differential hemodynamic effects. The role of the endothelium in the vascular effects of these agonists is still unclear. Primary cultures of rat aortal endothelial cells and Ea.hy 926 cells (a continuous endothelial cell line) were used to investigate the effects of Ap3A–Ap6A, adenosine triphosphate (ATP), and for comparison, arginine vasopressin (AVP) and angiotensin II (A II) on the intracellular Ca²⁺ concentration, [Ca²⁺]_i. Fura-2 was used as Ca²⁺ indicator. In rat aortal endothelial cells, ATP and Ap4A concentration dependently increased [Ca²⁺]_i with an initial peak followed by an elevated plateau. The half-maximal effects were reached at approximately 7 µmol/l for ATP and at approximately 10 µmol/l for Ap4A. The maximal peak effects at 100 µmol/l were 1,035 ± 413 nmol/l (n = 3) and 437 ± 271 nmol/l (n = 8) for ATP and Ap4A, respectively. At 100 µmol/l Ap3A and Ap6A slightly increased [Ca²⁺]_i, while Ap5A had no significant effect. The known endothelial agonists AVP (100 nmol/l) and A II (10 nmol/l) increased [Ca²⁺]_i initially by 1,549 ± 913 nmol/l (n = 7) and 209 ± 45 nmol/l (n = 9), respectively. In Ea.hy 926 cells an increase in [Ca²⁺]_i was obtained only with ATP (10 µmol/l) and with Ap4A (100 µmol/l). Ap3A, Ap5A, and Ap6A (each 100 µmol/l) and also AVP (100 nmol/l) and A II (10 nmol/l) had no significant effects in these cells. These results show that a considerable increase in [Ca²⁺]_i in endothelial cells can only be induced by Ap4A among the diadenosine polyphosphates, indicating that the vasoactive effects of only this polyphosphate could at least partly be mediated via Ca²⁺-dependent mechanisms in endothelial cells, comparable to the known effects of AVP, A II, and ATP. The fact that A II and AVP did not influence [Ca²⁺]_i in Ea.hy 926 cells is probably due to the loss of the respective receptors in this cell line.

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Section: Introductionmentioning

confidence: 75%

Section: Introductionmentioning

confidence: 97%

Effects of Diadenosine Polyphosphates on the Intracellular Ca<sup>2+</sup> Concentration in Endothelial Cells

Stachon

Stegemann²,

Hohage³

et al. 1998

Cell Physiol Biochem

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“…Indeed, previous studies have indicated that Ap 4 A reduces ischemic injury in the CNS and heart (Khattab et al, 1998;Ahmet et al, 2000a,b;Wang et al, 2003). Recently, Ap 4 A has been shown to have strong neuroprotective properties mediated by P1 and P4 receptors in primary neuronal culture used as models for stroke and Parkinson's disease (Wang et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Diadenosine Polyphosphate Analog Controls Postsynaptic Excitation in CA3-CA1 Synapses via a Nitric Oxide-Dependent Mechanism

Melnik

Wright²,

Tanner³

et al. 2006

J Pharmacol Exp Ther

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Previously, we have described the modulatory effect of diadenosine polyphosphates Ap 4 A and Ap 5 A on synaptic transmission in the rat hippocampal slices mediated by presynaptic receptors (Klishin et al., 1994). In contrast, we now describe how nonhydrolyzable Ap 4 A analog diadenosine-5Ј,5ٞ-P 1 ,P 4 -[␤,␤Ј-methylene]tetraphosphate (AppCH 2 ppA) at low micromolar concentrations exerts strong nondesensitizing inhibition of orthodromically evoked field potentials (OFPs) without affecting the amplitude of excitatory postsynaptic currents and antidromically evoked field potentials, as recorded in hippocampal CA1 zone. The effects of AppCH 2 ppA on OFPs are eliminated by a P2 receptor antagonist pyridoxal-phosphate-6-azophenyl-2Ј,4Ј-disulfonic acid (PPADS) but not mimicked by purinoceptor agonists ␣,␤-methylene-ATP and adenosine 5Ј-O-(3-thio)-triphosphate, indicating that a P2-like receptor is involved but not one belonging to the conventional P2X/P2Y receptor classes. Diadenosine polyphosphate receptor (P4) antagonist Ip 4 I (diinosine tetraphosphate) was unable to modulate AppCH 2 ppA effects. Thus, the PPADS-sensitive P2-like receptor for AppCH 2 ppA seems to control selectively dendritic excitation of the CA1 neurons. The specific nitric oxide (NO)-scavenger 2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide is shown to significantly attenuate AppCH 2 ppA-mediated inhibitory effects, indicating that NO is involved in the cascade of events initiated by AppCH 2 ppA. Further downstream mediation by adenosine A1 receptors is also demonstrated. Hence, AppCH 2 ppA-mediated effects involve PPADS-sensitive P2-like receptor activation leading to the production of NO that stimulates intracellular synthesis of adenosine, causing in turn postsynaptic A1 receptor activation and subsequent postsynaptic CA1 dendritic inhibition. Such spatially selective postsynaptic dendritic inhibition may influence dendritic electrogenesis in pyramidal neurons and consequently mediate control of neuronal network activity.

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“…The higher contractile potency of ApnA than their degradation products may be reflected by their considerably higher stability in the blood than, for instance, ATP, which is cleaved into adenosine and phosphate within seconds (Lü thje and Ogilvie, 1988;Lü thje, 1989). Although vasocontractile effects of ApnA on the local vascular level are well established, it was repeatedly confirmed that systemically applied ApnA only induce hypotensive effects (Kikuta et al, 1994;Khattab et al, 1998;Steinmetz et al, 2000c). Various studies with animal vascular preparations showed that the purinergically mediated vasoconstrictions are P2X purinoceptor-dependent (Bo and Burnstock, 1993;van der Giet et al, 1998;Steinmetz et al, 2000a,c).…”

Section: Discussionmentioning

confidence: 99%

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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Effects of Diadenosine Polyphosphates on Systemic and Regional Hemodynamics in Anesthetized Rats

Cited by 16 publications

References 22 publications

Effects of Diadenosine Polyphosphates on the Intracellular Ca<sup>2+</sup> Concentration in Endothelial Cells

Effects of Diadenosine Polyphosphates on the Intracellular Ca<sup>2+</sup> Concentration in Endothelial Cells

Diadenosine Polyphosphate Analog Controls Postsynaptic Excitation in CA3-CA1 Synapses via a Nitric Oxide-Dependent Mechanism

Vasoactivity of Diadenosine Polyphosphates in Human Small Mesenteric Resistance Arteries

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