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 physiological electrical activity. I(Kr) and I(Ks) were measured in guinea-pig ventricular myocytes at pacing cycle lengths (CL) of 1000 and 250 ms. 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 I(Kr) and I(Ks) to total 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 (constant diastolic interval). 5. In ramp clamp experiments, I(Kr) amplitude was directly proportional to repolarization rate at values within the low physiological range (< 1.0 V s(-1)); at higher repolarization rates proportionality became shallower and finally reversed. 6. When action potential duration (APD) was modulated by constant current injection (I-clamp), repolarization rates > 1.0 V s(-1) were associated with a reduced effect of I(Kr) block on APD. The effect of changes in repolarization rate was independent of CL and occurred in the presence of I(Ks) blockade. 7. In spite of its complexity, the behaviour of I(Kr) was accurately predicted by a numerical model based entirely on known kinetic properties of the current. 8. Both I(Kr) and I(Ks) may be increased at fast heart rates, but this may occur through completely different mechanisms. The mechanisms identified are such as to contribute to abnormal rate dependency of repolarization in prolonged repolarization syndromes.
Rocchetti
M
M
Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milan, Italy.
Besana
A
A
Gurrola
G B
GB
Possani
L D
LD
Zaza
A
A
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002839:Chromans / Q000494:pharmacology; D004553:Electric Conductivity; D006168:Guinea Pigs; D010880:Piperidines / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D011930:Reaction Time / Q000187:drug effects; D012604:Scorpion Venoms / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D016276:Ventricular Function
D002839:Chromans; D010880:Piperidines; D015221:Potassium Channels; D011725:Pyridines; D012604:Scorpion Venoms; D013449:Sulfonamides; C118951:ergotoxin, Centruroides noxius; C063968:E 4031; C103474:6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethylchromane