title: Adenosine-sensitive afterdepolarizations and triggered activity in guinea pig ventricular myocytes.
abstract: This study examines the cellular basis and specificity of the effects of adenosine on early afterdepolarizations (EADs), delayed afterdepolarizations (DADs), and triggered activity (TA) induced by various drugs with different mechanisms of action. Membrane potential and currents were measured in isolated guinea pig ventricular myocytes. Adenosine (10-100 microM) significantly (p less than 0.05) reduced the amplitude of DADs and suppressed TA induced by isoproterenol (10-50 nM) and forskolin (1 microM) but not those induced by dibutyryl cAMP (1 microM), ouabain (1-5 microM), and 7.2 mM [Ca2+]o. Adenosine also abolished EADs and TA induced by isoproterenol. In contrast, adenosine failed to abolish EADs and TA induced by quinidine (3 microM) or those that occurred spontaneously (i.e., in the absence of drugs). Transient inward current (ITi) was induced on repolarization after 2-second-long single depolarizing voltage steps or after 12-second-long trains of 300-msec depolarizing pulses. Concomitant with the attenuation of DADs, adenosine suppressed ITi caused by isoproterenol and forskolin but not those induced by ouabain, dibutyryl cAMP, and elevated [Ca2+]o. The amplitude of ITi was dependent on the magnitude of the activating voltage step, but the suppression of ITi by adenosine was not. The selective A1-adenosine receptor antagonist N-0861 (9-methyladenine derivative) antagonized the effects of adenosine on afterdepolarizations, ITi, and TA. In myocytes from guinea pigs treated with pertussis toxin, adenosine failed to attenuate DADs and ITi or abolish TA induced by isoproterenol or forskolin. In parallel experiments, isoproterenol (10 nM) raised cellular cAMP from 5.7 +/- 0.2 to 8.1 +/- 0.1 pmol and the selective A1 receptor agonist cyclopentyladenosine (5 microM) reduced it to 6.5 +/- 0.2 pmol (p less than 0.05). Thus, adenosine specifically attenuates afterdepolarizations and abolishes TA by suppressing ITiS that are associated with stimulation of adenylate cyclase via a pertussis toxin-sensitive A1 receptor-mediated action. In conclusion, the response of TA to adenosine may identify a mechanism of afterdepolarization related to stimulation of adenylate cyclase.
authors.affiliation: Department of Medicine, University of Florida, Gainesville 32610.
authors.forename: Y
authors.initials: Y
authors.lastname: Song
authors.forename: S
authors.initials: S
authors.lastname: Thedford
authors.forename: B B
authors.initials: BB
authors.lastname: Lerman
authors.forename: L
authors.initials: L
authors.lastname: Belardinelli
mesh_terms: D000200:Action Potentials; D000241:Adenosine / Q000494:pharmacology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology*; D005576:Colforsin / Q000494:pharmacology; D016048:Dideoxyadenosine / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D006329:Heart Conduction System / Q000187:drug effects*; D006352:Heart Ventricles / Q000166:cytology*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials; D011802:Quinidine / Q000494:pharmacology; D011983:Receptors, Purinergic / Q000187:drug effects; D016276:Ventricular Function
chemical_list: D011983:Receptors, Purinergic; D005576:Colforsin; D016048:Dideoxyadenosine; D011802:Quinidine; D000241:Adenosine; D007545:Isoproterenol