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Diadenosine tetra- and pentaphosphates affect contractility and bioelectrical activity in the rat heart via P2 purinergic receptors

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Abstract

Diadenosine polyphosphates (Ap(n)As) are endogenously produced molecules which have been identified in various tissues of mammalian organism, including myocardium. Ap(n)As contribute to the blood clotting and are also widely accepted as regulators of blood vascular tone. Physiological role of Ap(n)As in cardiac muscle has not been completely elucidated. The present study aimed to investigate the effects of diadenosine tetra- (Ap4A) and penta- (Ap5A) polyphosphates on contractile function and action potential (AP) waveform in rat supraventricular and ventricular myocardium. We have also demonstrated the effects of A4pA and Ap5A in myocardial sleeves of pulmonary veins (PVs), which play a crucial role in genesis of atrial fibrillation. APs were recorded with glass microelectrodes in multicellular myocardial preparations. Contractile activity was measured in isolated Langendorff-perfused rat hearts. Both Ap4A and Ap5A significantly reduced contractility of isolated Langendorff-perfused heart and produced significant reduction of AP duration in left and right auricle, interatrial septum, and especially in right ventricular wall myocardium. Ap(n)As also shortened APs in rat pulmonary veins and therefore may be considered as potential proarrhythmic factors. Cardiotropic effects of Ap4A and Ap5A were strongly antagonized by selective blockers of P2 purine receptors suramin and pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS), while P1 blocker DPCPX was not effective. We conclude that Ap(n)As may be considered as new class of endogenous cardioinhibitory compounds. P2 purine receptors play the central role in mediation of Ap4A and Ap5A inhibitory effects on electrical and contractile activity in different regions of the rat heart.

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Abbreviations

Ap(n)As:

Diadenosine polyphosphates

Ap4A:

Diadenosine tetraphosphate

Ap5A:

Diadenosine pentaphosphate

AP:

Action potential

PVs:

Pulmonary veins

P1 receptors:

Purine receptors type 1

P2 receptors:

Purine receptors type 2

dV/dtmax :

Upstroke velocity

APD50:

Action potential duration at 50 % repolarization

APD90:

Action potential duration at 90 % repolarization

LV:

Left ventricle

LVDP:

Left ventricle developed pressure

LVEDP:

Left ventricle end-diastolic pressure

RA:

Right auricle

LA:

Left auricle

IAS:

Interatrial septum

Ventr:

Ventricle

AF:

Atrial fibrillation

References

  • Abramochkin DV, Borodinova AA, Rosenshtraukh LV (2012) Effects of acetylcholinesterase inhibitor paraoxon denote the possibility of non-quantal acetylcholine release in myocardium of different vertebrates. J Comp Physiol B 182(1):101–108. doi:10.1007/s00360-011-0602-2

    Article  CAS  PubMed  Google Scholar 

  • Abramochkin DV, Nurullin LF, Borodinova AA, Tarasova NV, Sukhova GS, Nikolsky EE, Rosenshtraukh LV (2010) Non-quantal release of acetylcholine from parasympathetic nerve terminals in the right atrium of rats. Exp Physiol 95(2):265–273. doi:10.1113/expphysiol.2009.050302

    Article  CAS  PubMed  Google Scholar 

  • Arvola L, Bertelsen G, Hassaf D, Ytrehus K (2004) Positive inotropic and sustained anti-beta-adrenergic effect of diadenosine pentaphosphate in human and guinea pig hearts. Role of dinucleotide receptors and adenosine receptors. Acta Physiol 182(3):277–285. doi:10.1111/j.1365-201X.2004.01363.x

    Article  CAS  Google Scholar 

  • Brandts B, Borchard R, Dirkmann D, Wickenbrock I, Sievers B, van Bracht M, Prull MW, Trappe HJ (2003) Diadenosine-5-phosphate exerts A1-receptor-mediated proarrhythmic effects in rabbit atrial myocardium. Br J Pharmacol 139(7):1265–1272. doi:10.1038/sj.bjp.0705361

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Brandts B, Brandts A, Wellner-Kienitz MC, Zidek W, Schluter H, Pott L (1998) Non-receptor-mediated activation of IK(ATP) and inhibition of IK(ACh) by diadenosine polyphosphates in guinea-pig atrial myocytes. J Physiol 512(2):407–420. doi:10.1111/j.1469-7793.1998.407be.x

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Buvinic S, Briones R, Huidobro-Toro JP (2002) P2Y(1) and P2Y(2) receptors are coupled to the NO/cGMP pathway to vasodilate the rat arterial mesenteric bed. Br J Pharmacol 136(6):847–856. doi:10.1113/jphysiol.2006.105882

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Chung WC, Kermode JC (2005) Suramin disrupts receptor-G protein coupling by blocking association of G protein alpha and betagamma subunits. J Pharmacol Exp Ther 313(1):191–198. doi:10.1124/jpet.104.078311

    Article  CAS  PubMed  Google Scholar 

  • Conant AR, Fisher MJ, McLennan AG, Simpson AW (2000) Diadenosine polyphosphates are largely ineffective as agonists at natively expressed P2Y(1) and P2Y(2) receptors on cultured human saphenous vein endothelial cells. J Vasc Res 37(6):548–555. doi:10.1159/000054088

    Article  CAS  PubMed  Google Scholar 

  • Conant AR, Theologou T, Dihmis WC, Simpson AW (2008) Diadenosine polyphosphates are selective vasoconstrictors in human coronary artery bypass grafts. Vasc Pharmacol 48(4–6):157–164. doi:10.1016/j.vph.2008.01.005

    Article  CAS  Google Scholar 

  • Delicado EG, Miras-Portugal MT, Carrasquero LM, León D, Pérez-Sen R, Gualix J (2006) Dinucleoside polyphosphates and their interaction with other nucleotide signaling pathways. Pflugers Arch 452(5):563–572. doi:10.1007/s00424-006-0066-5

    Article  CAS  PubMed  Google Scholar 

  • Edgecombe M, McLennan AG, Fisher MJ (1999) Diadenosine polyphosphates and the control of cyclic AMP concentrations in isolated rat liver cells. FEBS Lett 457(3):455–458. doi:10.1016/S0014-5793(99)01099-6

    Article  CAS  PubMed  Google Scholar 

  • Flores NA, Stavrou BM, Sheridan DJ (1999) The effects of diadenosine polyphosphates on the cardiovascular system. Cardiovasc Res 42(1):15–26. doi:10.1016/S0008-6363(99)00004-8

    Article  CAS  PubMed  Google Scholar 

  • García-Villalón AL, Monge L, Fernández N, Salcedo A, Narváez-Sánchez R, Diéguez G (2009) Coronary response to diadenosine pentaphosphate after ischaemia-reperfusion in the isolated rat heart. Cardiovasc Res 81(2):336–343. doi:10.1093/cvr/cvn321

    Article  PubMed  Google Scholar 

  • Haissaguerre M, Jais P, Shah DC, Takahashi A, Hocini M, Quiniou G, Garrigue S, Le Mouroux A, Le Métayer P, Clémenty J (1998) Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 339(10):659–666. doi:10.1056/NEJM199809033391003

    Article  CAS  PubMed  Google Scholar 

  • Hoyle CH, Ziganshin AU, Pintor J, Burnstock G (1996) The activation of P1- and P2-purinoceptors in the guinea-pig left atrium by diadenosine polyphosphates. Br J Pharmacol 118(5):1294–1300

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Iwasaki Y, Nishida K, Kato T, Nattel S (2011) Atrial fibrillation pathophysiology: implications for management. Circulation 124(20):2264–2274. doi:10.1161/CIRCULATIONAHA.111.019893

    Article  CAS  PubMed  Google Scholar 

  • Jankowski J, Jankowski V, Laufer U, van der Giet M, Henning L, Tepel M, Zidek W, Schlüter H (2003) Identification and quantification of diadenosine polyphosphate concentrations in human plasma. Arterioscler Thromb Vasc Biol 23(7):1231–1238. doi:10.1161/01.ATV.0000075913.00428.FD

    Article  CAS  PubMed  Google Scholar 

  • Jovanovic A, Alekseev AE, Terzic A (1997) Intracellular diadenosine polyphosphates: a novel family of inhibitory ligands of the ATP-sensitive K+ channel. Biochem Pharmacol 54(2):219–225. doi:10.1016/S0006-2952(97)00262-1

    Article  CAS  PubMed  Google Scholar 

  • Jovanovic A, Jovanovic S, Mays DC, Lipsky JJ, Terzic A (1998) Diadenosine 5′,5″-P1,P5-pentaphosphate harbors the properties of a signaling molecule in the heart. FEBS Lett 423(3):314–318. doi:10.1016/S0014-5793(98)00114-8

  • Jovanovic A, Zhang S, Alekseev AE, Terzic A (1996) Diadenosine polyphosphate-induced inhibition of cardiac KATP channels: operative state-dependent regulation by a nucleoside diphosphate. Pflugers Arch 431(5):800–802. doi:10.1007/BF02253848

    CAS  PubMed  Google Scholar 

  • Knapp J, Bokník P, Linck B, Läer S, Müller FU, Neumann J, Vahlensieck U, Schlüter H, Zidek W, Schmitz W (1999) Inositol-1,4,5-trisphosphate increase by diadenosine tetraphosphate in preparations from failing human myocardium. Naunyn Schmiedeberg’s Arch Pharmacol 360(3):354–357. doi:10.1007/s002109900076

    Article  CAS  Google Scholar 

  • Laubinger W, Wang H, Welte T, Reiser G (2003) P2Y receptor specific for diadenosine tetraphosphate in lung: selective inhibition by suramin, PPADS, Ip5I, and not by MRS-2197. Eur J Pharmacol 468(1):9–14. doi:10.1016/S0014-2999(03)01624-8

    Article  CAS  PubMed  Google Scholar 

  • Lewis CJ, Gitterman DP, Schlüter H, Evans RJ (2000) Effects of diadenosine polyphosphates (Ap(n)As) and adenosine polyphospho guanosines (Ap(n)Gs) on rat mesenteric artery P2X receptor ion channels. Br J Pharmacol 129(1):124–130. doi:10.1038/sj.bjp.0702993

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Luo J, Jankowski J, Knobloch M, Van der Giet M, Gardanis K, Russ T, Vahlensieck U, Neumann J, Schmitz W, Tepel M, Deng MC, Zidek W, Schlüter H (1999) Identification and characterization of diadenosine 5′,5‴-P1,P2 -diphosphate and diadenosine 5′,5‴-P1,P3-triphosphate in human myocardial tissue. Faseb j 13(6):695–705

  • Luo J, Jankowski V, Güngär N, Neumann J, Schmitz W, Zidek W, Schlüter H, Jankowski J (2004) Endogenous diadenosine tetraphosphate, diadenosine pentaphosphate, and diadenosine hexaphosphate in human myocardial tissue. Hypertension 43(5):1055–1059. doi:10.1161/hyp.0000126110.46402.dd

    Article  CAS  PubMed  Google Scholar 

  • Lüthje J, Miller D, Oqilvie A (1987) Unproportionally high concentrations of diadenosine triphosphate (Ap3A) and diadenosine tetraphosphate (Ap4A) in heavy platelets. Consequences for in vitro studies with human platelets. Blut 54(4):193–200. doi:10.1007/BF00594193

    Article  PubMed  Google Scholar 

  • Lüthje J, Oqilvie A (1983) The presence of diadenosine 5′,5‴-P1,P3-triphosphate (Ap3A) in human platelets. Biochem Biophys Res Commun 115(1):253–260. doi:10.1016/0006-291X(83)90997-X

  • Mallet ML (2004) Proarrhythmic effects of adenosine: a review of the literature. Emerg Med J 21(4):408–410. doi:10.1136/emj.2004.016048

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • McDonald HA, Chu KL, Bianchi BR, McKenna DG, Briggs CA, Burgard EC, Lynch KJ, Faltynek C, Cartmell J, Jarvis MF (2002) Potent desensitization of human P2X3 receptors by diadenosine polyphosphates. Eur J Pharmacol 435(2–3):135–142. doi:10.1016/S0014-2999(01)01568-0

    Article  CAS  PubMed  Google Scholar 

  • Miras-Portugal MT, Gualix J, Pintor J (1998) The neurotransmitter role of diadenosine polyphosphates. FEBS Lett 430(1–2):78–82. doi:10.1016/S0014-5793(98)00560-2

    Article  CAS  PubMed  Google Scholar 

  • Mutafova-Yambolieva VN, Durnin L (2014) The purinergic neurotransmitter revisited: a single substance or multiple players? Pharmacol Ther 144(2):162–191. doi:10.1016/j.pharmthera.2014.05.012

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Nahum V, Tulapurkar M, Lévesque SA, Sévigny J, Reiser G, Fischer B (2006) Diadenosine and diuridine poly(borano)phosphate analogues: synthesis, chemical and enzymatic stability, and activity at P2Y1 and P2Y2 receptors. J Med Chem 49(6):1980–1990. doi:10.1021/jm050955y

    Article  CAS  PubMed  Google Scholar 

  • Neumann J, Meissner A, Bokník P, Gombosová I, Knapp J, Lüss H, Müller FU, Schlüter H, Zidek W, Rolf N, Van Aken H, Vahlensieck U, Schmitz W (1999) Inotropic effects of diadenosine tetraphosphate in isolated canine cardiac preparations. J Cardiovasc Pharmacol 33(1):151–156

    Article  CAS  PubMed  Google Scholar 

  • Pereira MF, Hernández MD, Pintor J, Miras-Portugal MT, Cunha RA, Ribeiro JA (2000) Diadenosine polyphosphates facilitate the evoked release of acetylcholine from rat hippocampal nerve terminals. Brain Res 879(1–2):50–54. doi:10.1016/S0006-8993(00)02726-8

    Article  CAS  PubMed  Google Scholar 

  • Pintor J, Miras-Portugal MT (2000) Receptors for diadenosine polyphosphates P2D, P2YApnA, P4 and dinucleotide receptors: are there too many? Trends Pharmacol Sci 21(4):135. doi:10.1016/S0165-6147(00)01453-X

    Article  CAS  PubMed  Google Scholar 

  • Schlüter H, Offers E, Brüggemann G, van der Giet M, Tepel M, Nordhoff E, Karas M, Spieker C, Witzel H, Zidek W (1994) Diadenosine phosphates and the physiological control of blood pressure. Nature 367(6459):186–188. doi:10.1038/367186a0

    Article  PubMed  Google Scholar 

  • Schotten U, Verheule S, Kirchhof P, Goette A (2011) Pathophysiological mechanisms of atrial fibrillation: a translational appraisal. Physiol Rev 91(1):265–325. doi:10.1152/physrev.00031.2009

    Article  PubMed  Google Scholar 

  • Stavrou BM (2003) Diadenosine polyphosphates: postulated mechanisms mediating the cardiac effects. Curr Med Chem Cardiovasc Hematol Agents 1(2):151–169. doi:10.2174/1568016033477513

    Article  CAS  PubMed  Google Scholar 

  • Stavrou BM, Lawrence C, Blackburn GM, Cohen T, Sheridan DJ, Flores NA (2001a) Coronary vasomotor and cardiac electrophysiologic effects of diadenosine polyphosphates and nonhydrolyzable analogs in the guinea pig. J Cardiovasc Pharmacol 37(5):571–584

    Article  CAS  PubMed  Google Scholar 

  • Stavrou BM, Sheridan DJ, Flores NA (2001b) Contribution of nitric oxide and prostanoids to the cardiac electrophysiological and coronary vasomotor effects of diadenosine polyphosphates. J Pharmacol Exp Ther 298(2):531–538

    CAS  PubMed  Google Scholar 

  • Steinmetz M, Gabriëls G, Le TV, Piechota HJ, Rahn KH, Schlatter E (2003) Vasoactivity of diadenosine polyphosphates in human small renal resistance arteries. Nephrol Dial Transplant 18(12):2496–2504. doi:10.1093/ndt/gfg405

    Article  CAS  PubMed  Google Scholar 

  • Steinmetz M, Janssen AK, Pelster F, Rahn KH, Schlatter E (2002) Vasoactivity of diadenosine polyphosphates in human small mesenteric resistance arteries. J Pharmacol Exp Ther 302(2):787–794. doi:10.1124/jpet.302.2.787

    Article  CAS  PubMed  Google Scholar 

  • Steinmetz M, Schlatter E, Boudier HA, Rahn KH, De Mey JG (2000) Diadenosine polyphosphates cause contraction and relaxation in isolated rat resistance arteries. J Pharmacol Exp Ther 294(3):1175–1181

    CAS  PubMed  Google Scholar 

  • Steinmetz M, Van Le T, Bierer S, De Mey JG, Schlatter E (2005) Prior vasorelaxation enhances diadenosine polyphosphate-induced contractility of rat mesenteric resistance arteries. Naunyn Schmiedeberg’s Arch Pharmacol 371(5):359–363. doi:10.1007/s00210-005-1059-1

    Article  CAS  Google Scholar 

  • Sumiyoshi R, Nishimura J, Kawasaki J, Kobayashi S, Takahashi S, Kanaide H (1997) Diadenosine polyphosphates directly relax porcine coronary arterial smooth muscle. J Pharmacol Exp Ther 283(2):548–556

    CAS  PubMed  Google Scholar 

  • Vahlensieck U, Bokník P, Gombosová I, Huke S, Knapp J, Linck B, Lüss H, Müller FU, Neumann J, Deng MC, Scheld HH, Jankowski H, Schlüter H, Zidek W, Zimmermann N, Schmitz W (1999) Inotropic effects of diadenosine tetraphosphate (AP4A) in human and animal cardiac preparations. J Pharmacol Exp Ther 288(2):805–813

    CAS  PubMed  Google Scholar 

  • van der Heyden MA, Wijnhoven TJ, Opthof T (2005) Molecular aspects of adrenergic modulation of cardiac L-type Ca2+ channels. Cardiovasc Res 65(1):28–39. doi:10.1016/j.cardiores.2004.09.028

    Article  PubMed  Google Scholar 

  • Vassort G (2001) Adenosine 5′-triphosphate: a P2-purinergic agonist in the myocardium. Physiol Rev 81(2):767–806

    CAS  PubMed  Google Scholar 

  • Vollmayer P, Clair T, Goding JW, Sano K, Servos J, Zimmermann H (2003) Hydrolysis of diadenosine polyphosphates by nucleotide pyrophosphatases/phosphodiesterases. Eur J Biochem 270(14):2971–2978. doi:10.1046/j.1432-1033.2003.03674.x

    Article  CAS  PubMed  Google Scholar 

  • von Kügelgen I (2006) Pharmacological profiles of cloned mammalian P2Y-receptor subtypes. Pharmacol Ther 110(3):415–432

    Article  Google Scholar 

  • von Kügelgen I, Hoffmann K (2015) Pharmacology and structure of P2Y receptors. Neuropharmacology. doi:10.1016/j.neuropharm.2015.10.030

    Google Scholar 

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Acknowledgments

This study was supported by the Russian Science Foundation [14-15-00268 to DVA].

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Authors and Affiliations

  1. Department of Human and Animal Physiology, Lomonosov Moscow State University, Leninskiye gory 1, building 12, Moscow, 119991, Russia

    Ksenia B. Pustovit, Vladislav S. Kuzmin & Denis V. Abramochkin

  2. Department of Physiology, Pirogov Russian National Research Medical University, Ostrovitjanova 1, Moscow, 117997, Russia

    Ksenia B. Pustovit, Vladislav S. Kuzmin & Denis V. Abramochkin

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  1. Ksenia B. Pustovit
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  2. Vladislav S. Kuzmin
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  3. Denis V. Abramochkin
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Correspondence to Denis V. Abramochkin.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants performed by any of the authors.

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Pustovit, K.B., Kuzmin, V.S. & Abramochkin, D.V. Diadenosine tetra- and pentaphosphates affect contractility and bioelectrical activity in the rat heart via P2 purinergic receptors. Naunyn-Schmiedeberg's Arch Pharmacol 389, 303–313 (2016). https://doi.org/10.1007/s00210-015-1199-x

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