Mechanisms underlying the modulation of arrhythmogenic events by components of ischemia in guinea pig cardiac myocytes

Abstract

The effects of some components of ischemia on the oscillatory (Vos) and nonoscillatory (V(ex)) potentials and respective currents (Ios and Iex), as well as their mechanisms, were studied in guinea pig isolated ventricular myocytes by means of a single-microelectrode, discontinuous voltage clamp method. Repetitive activations induced not only Vos and Ios, but also V(ex) and Iex. A small decrease in resting potential caused an immediate increase in Vos followed by a gradual increase due to the longer action potential. Immediate and gradual increases in Ios also occurred during voltage clamp steps. A small depolarization increased Vos and V(ex), and facilitated the induction of spontaneous discharge by fast drive. At Vh where INa is inactivated, depolarizing steps induced larger Ios and Iex, indicating the importance of the Na-independent Ca loading. High [K]o decreased the resting potential, but also Vos, V(ex), Ios, Iex, and ICa. In high [K]o, depolarization still increased Vos and V(ex). Norepinephrine (NE) enhanced Vos and V(ex), and also Ios and Iex, during voltage clamp steps. High [K]o antagonized NE effects, and NE those of high [K]o. In conclusion, on depolarization, Vos and Ios immediately increase through a voltage-dependent mechanism; and then Vos and Ios gradually increase, apparently through an increased Ca load related to the longer action potentials and the Na-Ca exchange. The depolarization induced by V(ex) may contribute to increase Vos size. Vos and V(ex) are similarly influenced by different procedures that modify Ca load. The arrhythmogenic events are enhanced by the simultaneous presence of depolarization, faster rate, or NE. Instead, high [K]o decreases Vos and V(ex) by decreasing ICa and opposes the effects of NE. The voltage clamp results show that potentiation and antagonism between different components of ischemia are due primarily to changes in Ca loading and not to changes in action potential configuration.