Experimental Disease Models

There are a number of levels and experimental approaches which are used in attempts to understand arrhythmic mechanisms and antiarrhythmic drug effects, and for the prediction of drug effects on the arrhythmias seen in humans. These can be considered according to a hierarchy of approaches:

• using computer modeling of cardiac electrophysiology, and/or arrhythmias, plus computer modeling of molecular targets (ion channels), and their interactions with compounds;

• studying ionic currents, and their characteristics, in single ion channels (expressed or wild-type) using patch clamp techniques;

• measuring whole cell currents, and their characteristics, using expressed or wild-type channels in special cells, or in isolated cardiac cells;

• measuring intracellular action potentials in cardiac tissue in vitro or in vivo;

• determining electrophysiological properties such as automaticity, excitability, conduction velocity, and refractoriness using electrical stimulation techniques in vitro in isolated cardiac tissue and/or isolated hearts, or in vivo on intact hearts;

• inducing arrhythmias in isolated or intact hearts, using various techniques such as chemical arrhythmogens or surgery to induce arrhythmic damage. The latter is used to stretch atria and ventricles, or create myocardial ischemia and infarction. This can be combined with electrical stimulation of the heart directly or indirectly through cardiac nerves.

No single one of these techniques definitively provides an unequivocal answer as to whether an experimental drug has antiarrhythmic actions in humans. Instead they have to be used in concert to build up a coherent picture of the clinical potential of a particular new chemical entity. The question of which technique to use depends upon the goal to be achieved. If, for example, one has decided to create a compound that acts potently and specifically on a particular ion channel it may be sufficient to concentrate on that channel. Of course the specificity for this chosen channel has to be compared with actions on all cardiac channels. This can be a daunting endeavor although it is being made easier as more channels become available in functional high-throughput assays.13 The generally promiscuous nature of binding of ion channel blockers to channels, in terms of channel type and channel sites to which they bind, makes simple binding studies inadequate. Predictive in silico modeling is being used more often in terms of modeling putative drugs, binding sites, and pharmacological actions.14 At the moment these approaches may be more in the nature of ad hoc rationalizations rather than predictions.

There are various approaches to modeling arrhythmias and to screen for antiarrhythmic actions. These screens range from precisely defined in vitro situations to ill-defined in vivo ones, as illustrated below:

1. Use of particular channels expressed in human embryonic kidneys cells or in high-throughput screens.

2. Use of the less well-defined models from patch clamp studies on wild-type ionic currents to intracellular potential studies in cardiac tissue preparations.

3. Use of isolated hearts or whole animals to screen for potential antiarrhythmic drug actions by determining their electrophysiological effects on the ECG or on responses to electrical stimulation.

4. Use of various arrhythmia models in isolated hearts or whole animals.

The in vivo models include induction of arrhythmias by use of electrical stimulation, arrhythmogenic chemicals, or pathological stimuli. For example, atrial arrhythmias can be induced by drugs and vagal stimulation, whereas heart attacks can be mimicked with regional myocardial ischemia, and/or infarction, by temporary or permanent occlusion of a coronary artery.

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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