Arrhythmias associated with myocardial ischaemia and infarction

Principles of Safety Pharmacology

“…If, on the other hand, the model regularly gives false negatives then there will be no products to test in man, and the model will eventually be abandoned and superseded by another. Model competition is inherent in academia and industry; for example, in antiarrhythmic drug discovery researchers have had species issues (dog vs cat vs rat vs pig); conscious vs anesthetized vs isolated heart preparations; myocardial ischemia vs infarction vs reperfusion vs programmed electrical stimulation (PES), with continuous re‐appraisal of models ( Johnston et al ., 1983 ; Botting et al ., 1985 ; Chung et al ., 1993 ; Bellemin‐Baurreau et al ., 1994 ; Curtis, 1998 ; Billman, 2006 ; Hamlin, 2007 ). As yet there has been little equivalent assessment in Safety Pharmacology.…”

Pharmacological and toxicological activity of RSD921, a novel sodium channel blocker

“…It is generally accepted that widening of the QRS interval reflects a depression of the phase 0 sodium currents and a reduction in ventricular conduction velocity [56]. PR interval prolongation in the hearts of small animals is primarily derived from sodium channel blockade (unlike larger mammals) and depression of conduction in atrial tissue [57]. Although it has been observed that L-type calcium channel blockers prolong the PR interval in the rat by way of depressing inward A–V nodal calcium current [58], this mechanism is unlikely to play a role in the case of RSD921 as it occurs at high doses of these drugs associated with non-selective channel block.…”

Principles of Safety Pharmacology

“…Changes in this interval, in most species, reflect changes in Ca 2+ channel function; however, in the rat Na + channels are dominant (Botting et al 1985). It generally represents conduction time across the AVN.…”