title: Activation of purinergic receptors by ATP induces ventricular tachycardia by membrane depolarization and modifications of Ca2+ homeostasis.
abstract: Cardiac myocytes are continuously exposed to extracellular nucleotides secreted by the myocytes themselves, nerve terminals, or platelets and other blood cells during coronary perfusion, and the concentrations of such extracellular nucleotides are known to increase during cardiac ischemia and hypoxia. The effects of the extracellular nucleotides ATP, ADP, UTP, and adenosine on ventricular arrhythmogenic properties were explored in 36 Langendorff-perfused mouse hearts using monophasic action potential recording. Extracellular nucleotides induced arrhythmic phenomena in form of ectopic activity and ventricular tachycardia in a potency order of ATP (n=7) > ADP (n=5) > UTP (n=3) approximately adenosine (n=3). The purinergic receptor antagonists suramin and pyridoxal phosphate-6-azo(benzene-2,4-disulphonic acid) reduced the incidence of ATP-triggered arrhythmias. In isolated ventricular myocytes, ATP induced sustained increases in diastolic Ca2+ and triggered multiple Ca2+ waves, which were inhibited by suramin but not by the L-type Ca2+ channel antagonist nifedipine. In whole-cell patch clamp experiments, extracellular ATP induced two distinct types of inward currents, which were inhibited by suramin and PPADS, suggesting activation of P2X receptors. ATP also induced delayed after-depolarizations and ectopic action potentials in current clamped ventricular myocytes. In conclusion, extracellular ATP activates purinergic receptors and induces arrhythmic activity through modifications of Ca2+ homeostasis and an activation of depolarizing membrane currents.
authors.affiliation: Department of Biochemistry, Hopkins Building; University of Cambridge, Tennis Court Road, Cambridge, CB2 1QW, UK. isg22@cam.ac.uk
authors.forename: Iman S
authors.initials: IS
authors.lastname: Gurung
authors.forename: Asli
authors.initials: A
authors.lastname: Kalin
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Grace
authors.forename: Christopher L-H
authors.initials: CL
authors.lastname: Huang
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000244:Adenosine Diphosphate / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000517:prevention & control; D002118:Calcium / Q000378:metabolism*; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D018613:Microscopy, Confocal; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D058913:Purinergic Agonists; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D011983:Receptors, Purinergic / Q000378:metabolism*; D013498:Suramin / Q000494:pharmacology; D017180:Tachycardia, Ventricular / Q000139:chemically induced*
chemical_list: D058913:Purinergic Agonists; D011983:Receptors, Purinergic; C077792:pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid; D011732:Pyridoxal Phosphate; D013498:Suramin; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D002118:Calcium