MECHANISM OF CURRENT-INDUCED EARLY AFTERDEPOLARIZATIONS IN GUINEA-PIGVENTRICULAR MYOCYTES

We investigated possible ionic mechanisms that cause early afterdepola rizations (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 cur rent was adjusted to measure the threshold potential (V-th) associated with the minimum inward current required for inducing EADs [threshold current (I-th)] and also the magnitude of EADs at V-th 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 membran e Ca2+ channel current (verapamil 1.1 x 10(-5) M and nisoldipine 5 x 1 0(-7) M) reduced or abolished EADs arising from -30 or -20 mV. Cells t hat generated delayed afterdepolarizations (DADs) in the absence of de polarizing current after 20 stimulations at 5 Hz either in central sol ution or following interventions associated with Ca2+ loading (reduced extracellular [K+] or increased extracellular [Ca2+]) also developed a marked shift in V-th 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 (rt = 25), P < 0.001]. Ca2+ loading also increased the magnitude of EADs arising from V-th and -20 mV. Exposure to quinidine (1.23 x 10(-5) M), which b locks both Na+ and delayed rectifier K+ channels, significantly reduce d I-th but had only minimal effect on the magnitude of EADs. Our resul ts suggest that L-type Ca2+ channel current and [Ca2+]-sensitive inwar d current associated with release of Ca2+ from the sarcoplasmic reticu lum 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.