Reverse use-dependency

TRIaD triangulation, reverse use dependence, instability and dispersion... 

Hondeghem, L.M. and Hoffmann, P. (2003) Blinded test in isolated female rabbit heart reliably identifies action potential duration prolongation and proarrhythmic drugs importance of triangulation, reverse use dependence, and instability. Journal of Cardiovascular Pharmacology, 41, 14—24. 

A next-level assay is usually an isolated heart/cardiac tissue preparation. The canine Purkinje fiber assay (GLP) measures several action potential parameters, like resting membrane potential, upstroke velocity, action potential duration and shape, but also if a drug acts reverse-use dependently [72]. Based on changes of the action potential shape it is possible to conclude which ion channels are modulated (e.g., L-type calcium channel block would abolish the plateau phase). The papillary muscle assay (e.g., guinea pigs) determines similar parameters [73]. 

Dofetilide blocks IKr in all myocardial tissues. It blocks open channels, and its binding and release from the channels is voltage dependent. The effects of dofetilide are exaggerated when the extracellular potassium concentration is reduced, which is important, as many patients may be receiving diuretics concurrently. Conversely, hyperkalemia decreases the effects of dofetilide, which may limit its efficacy when local hyperkalemia occurs, such as during myocardial ischemia. Dofetilide demonstrates reverse use dependence, that is, less influence on the action potential at faster heart... 

Amiodarone markedly prolongs the action potential duration (and the QT interval on the ECG) by blockade of IKr. During chronic administration, IKs is also blocked. The action potential duration is prolonged uniformly over a wide range of heart rates that is, the drug does not have reverse use-dependent action. In spite of its present classification as a class 3 agent, amiodarone also significantly blocks... 

Hondeghem LM, Snyders DJ. Class III Antiarrhythmic agents have a lot of potential, but a long way to go reduced effectiveness and dangers of reverse use-dependence. Circulation 1990 81 686-690. 

Whereas the measured characteristics of instability, triangulation and reverse use-dependency contribute to proarrhythmic activity of a drug, their relative... 

Although the efficacy of IKr blockade is reduced at fast pacing rates due to reverse use dependence (i.e., APD-prolonging effects are least pronounced at fast stimulation rates), IKs blockade may be expected to be more useful in prolonging APD at fast rates, whereas IKs accumulates due to slow deactivation (30,92). 

Readouts-. APDX Duration from midpoint of upstroke till x% of repolarization (where x is 10, 20, 30, 40, 50, 60, 70, 80, and 90), Triangulation repolarization time from APD30 to APD90. Reverse use dependence Difference between APD60 of the first 10 and last 20 APs (30 pulse train, 1 Hz). Ectopics (After 80 ms of stimulus the heart beats number where no upstroke of the AP) average ectopics per minute from 7 to 10 min of drug exposure. 

---