Mechanism of the use dependence of Ca2+ current in guinea-pig myocytes.

1. The mechanism of the use-dependent reduction and facilitation of the calcium current (iCa) in single guinea-pig myocytes described by Fedida, Noble & Spindler (1988) has been examined by varying [Ca2+]o, [Ca2+]i and iCa. 2. Moderate enhancement of [Ca2+]i and [Ca2+]i changes produced by increasing [Ca2+]o reduces iCa and enhances the use-dependent reduction. 3. Intracellular calcium overload, produced by reducing [Na+]o, greatly reduces iCa and almost totally eliminates the use-dependent variations. 4. Use-dependent reduction of iCa is also smaller after substituting external Ba2+ ions for Ca2+ ions. 5. When [Ca2+]i is buffered by intracellular EGTA sufficient to eliminate other [Ca2+]i-dependent processes, such as contraction and Na+-Ca2+ exchange, some use-dependent reduction of iCa remains, although the effect is smaller. Use-dependent facilitation of iCa is more prominent in the presence of internal EGTA. 6. The facilitation of iCa is abolished by Ba2+ replacement of Ca2+ and by the beta-adrenoceptor agonist isoprenaline. This suggests that the facilitation is mediated by Ca2+ entry itself rather than membrane voltage. Facilitation is evident as a delay of current relaxation, even in the presence of internal EGTA.