EXTRACELLULAR DIADENOSINE TETRAPHOSPHATE SUPPRESSES ECTOPIC PROARRHYTHMICITY IN THE MYOCARDIAL TISSUE OF THE PULMONARY VEINS IN ADULT BUT NOT IN NEONATAL RATS

Diadenosine tetraphosphate (Ap4A) belongs to a group of endogenous purine compounds that have been recently considered as new neurotransmitters or cotransmitters in autonomic nervous system. It has been shown that Ap4A affects electrophysiology of a pacemaker and working myocardium; modulates adrenergic control of the heart in adult mammals. Nevertheless, the physiological role of Ap4A in regulation of bioelectric properties in pulmonary veins (PV) myocardium has not still been investigated. It is well known that myocardial tissue in the wall of the PV acts as source of the ectopic proarrhythmic activity that underlies supraventricular arrhythmias like atrial fibrillation. The aim of the present study was to elucidate the effects Ap4A on bioelectrical properties and proarrhythmic ectopy in PV in adults and at early postnatal ontogenesis. Thus, the action potentials were recorded with use of standard microelectrode technique in multicellular isolated PV preparations from male Wistar rats at postnatal day 1-, 7-, 14-, 21- and, also, from 60-day-old animals, which were considered as mature. The application of Ap4A caused significant reduction of action potential duration in PV preparations from rats of all ages. Also, Ap4A caused significant resting membrane potential hyperpolarization in quiescent PV preparations from 14-, 21- and 60-day-old rats. In addition, Ap4A caused complete and significant suppression of ectopic automaticity caused by preliminary noradrenaline administration in PV from 21- and 60-day-old rats, but Ap4A was unable to alter spontaneous intrinsic activity in PV from neonate (1-day-old) rats. The Ap4Acaused attenuation of noradrenaline-induced ectopy in PV was accompanied by substantial resting membrane potential hyperpolarization in all cases. Our results allow suggesting that the release of Ap4A as cotransmitter from autonomic nerves endings can reduce proarrhythmic ectopy caused by sympathetic stimulation of the PV myocardium in vivo.

1. Szalata M. Dinucleoside polyphosphates: occurrence, metabolism and function // Postepy Biochem. 2001. Vol. 47. N 1. P. 105–113.

2. Abramochkin D.V., Pustovit K.B., Filatova T.S. Effects of diadenosine polyphosphates on inward rectifier potassium currents in rat cardiomyocytes // Moscow Univ. Biol. Sci. Bull. 2015. Vol. 70. N 4. P. 153–157.

3. Pakhomov N.V., Pustovit K.B., Abramochkin D.V., Kuz`min V.S. The role of diadenosine pentaphosphate and nicotinamide adenine dinucleotide (NAD+) as potential nucleotide comediators in the adrenergic regulation of cardiac function // Neurochem. J. 2017. Vol. 11. N 1. P. 63–71.

4. Flores N.A., Stavrou B.M., Sheridan D.J. The effects of diadenosine polyphosphates on the cardiovascular system // Cardiovasc. Res. 1999. Vol. 42. N 1. P. 15–26.

5. Abramochkin D.V. Karimova V.M., Filatova T.S., Kamkin A. Diadenosine pentaphosphate affects electrical activity in guinea pig atrium via activation of potassium acetylcholine-dependent inward rectifier // J. Physiol. Sci. 2017. Vol. 67. N 4. P. 523–529.

6. Hoyle C.H. Ziganshin A.U., Pintor J., Burnstock G. The activation of P1- and P2- purinoceptors in the guinea-pig left atrium by diadenosine polyphosphates // Br. J. Pharmacol. 1996. Vol. 118. N 5. P. 1294–1300.

7. Erlinge D., Burnstock G. P2 receptors in cardiovascular regulation and disease // Purinergic Signal. 2008. Vol. 4. N 1. P. 1–20.

8. Vassort G. Adenosine 5’-triphosphate: a P2-purinergic agonist in the myocardium // Physiol. Rev. 2001. Vol. 81. N 2. P. 767–806.

9. 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 Schmiedebergs Arch. Pharmacol. 2016. Vol. 389. N 3. P. 303–313.

10. Pakhomov N., Pustovit K., Potekhina V., Filatova T., Kuzmin V., Abramochkin D. Negative inotropic effects of diadenosine tetraphosphate are mediated by protein kinase C and phosphodiesterases stimulation in the rat heart // Eur. J. Pharmacol. 2018. Vol. 820. P. 97–105.

11. Pelleg A., Katchanov G., Xu J. Autonomic neural control of cardiac function: modulation by adenosine and adenosine-5-triphosphate // Am. J. Cardiol. 1997. Vol. 9149. N 2. Suppl. 1. P. 11– 14.

12. Neumann J., Meissner A., Boknik P., Gombosová I., Knapp J., Lüss H., Müller F.U., Schlüter H., Zidek W., Rolf N., Van Aken H., Vahlensieck U., Schmitz W. Inotropic effects of diadenosine tetraphosphate in isolated canine cardiac preparations // J. Cardiovasc. Pharmacol. 1999. Vol. 33. N 1. P. 151–156.

13. Masani F. Node-like cells in the myocardial layer of the pulmonary vein of rats: an ultrastructural study // J. Anat. 1986. Vol. 145. P. 133–142.

14. Haissaguerre M., Jais P., Shah D.C. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins // N. Engl. J. Med. 1998. Vol. 339. N 10. P. 659–666.

15. Maupoil V., Bronquard C., Freslon J.L, Cosnay P., Findlay I. Ectopic activity in the rat pulmonary vein can arise from simultaneous activation of alpha1- and beta1-adrenoceptors // Br. J. Pharmacol. 2007. Vol. 150. N 7. P. 899– 905.

16. Ehrlich J.R., Cha T.J., Zhang L., Chartier D., Melnyk P., Hohnloser S.H., Nattel S. Cellular electrophysiology of canine pulmonary vein cardiomyocytes: action potential and ionic current properties // J. Physiol. 2003. Vol. 551. N 3. P. 801–813.

17. Karimova V.M., Pustovit K.B., Abramochkin D.V., Kuz’min V.S. Effect of Purine co-transmitters on automatic activity caused by norepinephrine in myocardial sleeves of pulmonary veins // Bull. Exp. Biol. Med. 2017. Vol. 162. N 5. P. 589-593.

18. Robinson R.B. Autonomic receptor– effector coupling during post-natal development // Cardiovasc. Res. 1996. Vol. 31. P. 68–76.

19. Webb T.E., Boluyt M.O., Barnard E.A. Molecular biology of P2Y purinoceptors: expression in rat heart // J. Auton. Pharmacol. 1996. Vol. 16. N 6. P. 303–307.

20. Pustovit K.B., Abramochkin D.V. Effects of nicotinamide adenine dinucleotide (NAD+) and diadenosine tetraphosphate (Ap4A) on electrical activity of working and pacemaker atrial myocardium in guinea pigs // Bull. Exp. Biol. Med. 2016. Vol. 160. N 6. P. 733–736.

21. Pustovit K.B., Potekhina V.M., Pakhomov N.V., Kuzmin V.S. Effects of extracellular diadenosine tetraphosphate on action potentials in the atrial and ventricular myocardium of the rat heart during early postnatal ontogenesis // Moscow Univ. Biol. Sci. Bull. 2018. Vol. 73. N 1. P. 43–49.

22. Nerbonne J.M. Regulation of voltage-gated K+ channel expression in the developing mammalian myocardium // J. Neurobiol. 1998. Vol. 37. N 1. P. 37–59.