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 μM) significantly (p<0.05) reduced the amplitude of DADs and suppressed TA induced by isoproterenol (10–50 nM) and forskolin (1 μM) but not those induced by dibutyryl cAMP (1 μM), ouabain (1–5 μM), and 7.2 mM [Ca2+]0. Adenosine also abolished EADs and TA induced by isoproterenol. In contrast, adenosine failed to abolish EADs and TA induced by quinidine (3 μM) 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 ITicaused by isoproterenol and forskolin but not those induced by ouabain, dibutyryl cAMP, and elevated [Ca2+]0The amplitude of ITiwas dependent on the magnitude of the activating voltage step, but the suppression of ITiby 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 ITior 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 A1receptor agonist cyclopentyladenosine (5 μM) reduced it to 6.5 ± 0.2 pmol (p < 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 A, receptor-mediated action. In conclusion, the response of TA to adenosine may identify a mechanism of afterdepolarizations related to stimulation of adenylate cyclase.