We investigated possible ionic mechanisms that cause early afterdepolarizations (EADs) following the injection of constant inward current in guinea pig ventricular myocytes by several interventions that affect failure of action potential repolarization. The amount of constant current was adjusted to measure the threshold potential (Vth) associated with the minimum inward current required for inducing EADs [threshold current (Ith)] and also the magnitude of EADs at Vth and following adjustment of current to generate takeoff potentials of -30 and -20 mV. Interventions associated with either inhibition of Ca2+ release from the sarcoplasmic reticulum (ryanodine 5 x 10(-6) M) or L-type membrane Ca2+ channel current (verapamil 1.1 x 10(-5) M and nisoldipine 5 x 10(-7) M) reduced or abolished EADs arising from -30 or -20 mV. Cells that generated delayed afterdepolarizations (DADs) in the absence of depolarizing current after 20 stimulations at 5 Hz either in control solution or following interventions associated with Ca2+ loading (reduced extracellular [K+] or increased extracellular [Ca2+]) also developed a marked shift in Vth of current-induced EADs at 1-Hz stimulation to more negative potentials [60.3 +/- 10.7 mV (mean +/- SD, n = 17) vs. -41.7 +/- 6.4 mV in cells without DADs in control solution (n = 25), P < 0.001]. Ca2+ loading also increased the magnitude of EADs arising from Vth and -20 mV. Exposure to quinidine (1.23 x 10(-5) M), which blocks both Na+ and delayed rectifier K+ channels, significantly reduced Ith but had only minimal effect on the magnitude of EADs. Our results suggest that L-type Ca2+ channel current and [Ca2+]-sensitive inward current associated with release of Ca2+ from the sarcoplasmic reticulum are the major currents that cause this form of EADs, and that Ca2+ loading promotes the development of large EADs likely to propagate to normal tissue.