Voltage-independent effects of extracellular K⁺ on the Na⁺ current and phase 0 of the action potential in isolated cardiac myocytes

A rise in [K⁺](o), by depolarizing the resting membrane potential and partially inactivating the inward Na⁺ current (I(Na)), is believed to play a critical role in slowing conduction during myocardial ischemia. In multicellular ventricular preparations, elevation of [K⁺](o) has been suggested to decrease V(max) to a greater extent than expected from membrane depolarization alone. The mechanism of this voltage-independent effect of [K⁺](o) is currently unknown, and its significance in single cardiac cells has not been determined. We have examined the voltage-independent effects of elevated [K⁺](o) on I(Na) and the action potential upstroke in isolated rabbit atrial and ventricular myocytes under voltage- and current-clamp conditions. Superfusate [K⁺] was varied from 5 mmol/L to 14 or 24 mmol/L, whereas [Na⁺] was maintained at 150 mmol/L. In cultured atrial cells and excised outside-out patches from freshly isolated atrial and ventricular cells, the amplitude and kinetics of I(Na) were unchanged by elevation of [K⁺](o). In atrial cells, action potentials elicited from a holding potential of -70 mV had a similar V(max) (114.9±5.7 versus 112.2±4.8 V/s, mean±SEM, n=6) and action potential amplitude (115.0±2.4 versus 113.4±3.9 mV) in 5 and 24 mmol/L [K⁺](o). In contrast, in ventricular cells at a holding potential of -70 mV, increasing [K⁺](o) from 5 to 14 mmol/L decreased V(max) from 161.8±18.0 to 55.3±5.0 V/s (n=7, P<.001) and action potential amplitude from 128.1±1.3 to 86.6±5.4 mV (P<.001). This voltage- independent decrease in V(max) and action potential amplitude induced by elevated [K⁺](o) was abolished in the presence of 1 mmol/L Ba²⁺, suggesting that it is attributable to an increased background K⁺ conductance. We conclude that elevation of [K⁺](o) to levels expected during ischemia causes a marked voltage-independent depression of V(max) in ventricular cells, which may, in turn, contribute to the slowing of myocardial conduction characteristics of early ischemia.