Early afterdepolarizations: mechanism of induction and block. A role for L-type Ca2+ current.

Abstract

Early afterdepolarizations (EADs) are a type of triggered activity found in heart muscle. We used voltage-damped sheep cardiac Purkinje fibers to examine the mechanism underlying EADs induced near action potential plateau voltages with the Ca 2+ current agonist Bay K 8644 and the effect of several interventions known to suppress or enhance these EADs. Recently, we reported a model for inducing EADs in sheep and canine cardiac Purkinje fibers using the Ca 2+ current agonist Bay K 8644. 3 Bay K 8644 produced concentration-and frequency-dependent lengthening of action potential duration and flattening of the plateau. At low stimulation frequencies, EADs were induced from an average take-off potential of -34 mV. Several drug and ionic interventions that affect different membrane currents suppress or enhance the induction of EADs with Bay K 8644, and these observations were similar to results obtained in other experimental EAD models (e.g., Cs + , quinidine, and low [K] o ). The EAD peak voltage also showed marked dependence on its take-off potential. We interpreted these results to suggest that EAD induction required two phases: 1) an initiation or conditioning phase controlled by the sum of membrane currents present at the action potential plateau and characterized by its lengthenby guest on May 9, 2018

Calcium-Voltage Coupling in the Genesis of Early and Delayed Afterdepolarizations in Cardiac Myocytes

“…It is well known that LCC window current is a key component for EADs (17)(18)(19)(20)(21), but all other currents during the plateau also contribute to the formation of the EADs (21,41). Using bifurcation analysis (21,44), we have previously identified the bifurcations that initiate and terminate the voltage oscillations, and characterized the contribution of each ionic current in generating these bifurcations.…”

Endothelial nitric oxide synthase decreases β-adrenergic responsiveness via inhibition of the L-type Ca2+ current

“…Abnormal L-type Ca 2ϩ channel activity can cause EADs (24). Thus we examined the effects of NOS3 signaling on the I Ca in myocytes from WT and NOS3 Ϫ/Ϫ mice.…”

“…1). Previous work has shown that EADs can result from abnormal I Ca activity (24). In addition to EADs, increased Ca 2ϩ influx via I Ca can also lead to aftercontractions.…”

“…Studies have shown that EADs can be induced using the L-type Ca 2ϩ channel agonist BAY K 8644 (15,24). Additionally, studies have shown that L-type Ca 2ϩ channel antagonists can significantly decrease the occurrence of EADs (24,44).…”

“…High sympathetic activation and specifically increased I Ca can be detrimental to cardiac myocytes, leading to arrhythmias (24). Interestingly, transgenic mice overexpressing NOS3 demonstrated a lower incidence of spontaneous arrhythmic contractions in cultured neonatal myocytes (32).…”