Rate dependency of delayed rectifier currents during the guinea-pig ventricular action potential

1. The action potential clamp technique was exploited to evaluate the rate dependency of delayed rectifier currents (I-Kr and I-Ks) during physiologic al electrical activity. I-Kr and I-Ks were measured in guinea-pig ventricul ar myocytes at. pacing cycle lengths (CL) of 1000 and 250 ins. 2. A shorter CL, with the attendant changes in action potential shape, was associated with earlier activation and increased magnitude of both I-Kr and I-Ks. Nonetheless, the relative contributions of and I-Kr and I-Ks to tota l transmembrane current were independent of CL. 3. Shortening of diastolic interval only (constant action potential shape) enhanced I-Ks, but not I-Kr. 4. I-Kr was increased by a change in the action potential shape only (const ant. diastolic interval). 5. In ramp clamp experiments, I-Kr amplitude was directly proportional to r epolarization rate at values within the low physiological range (<1.0 V s(- 1)); at higher repolarization rates proportionality became shallower and fi nally reversed. 6. When action potential duration (APD) was modulated by constant current, injection (I-clamp), repolarization rates > 1.0 V s(-1) were associated wit h a reduced effect of I-Kr block on APD. The effect of changes in repolariz ation rate was independent of CL and occurred in the presence of I-Ks block ade. 7. In spite of its complexity, the behaviour of I-Kr was accurately predict ed by a numerical model based entirely on known kinetic properties of the c urrent. 8. Both I-Kr and I-Ks tray he increased at fast heart rates, but this may o ccur through completely different mechanisms. The mechanisms identified are such as to contribute to abnormal rate dependency of repolarization in pro longed repolarization syndrome.