BACKGROUND AND PURPOSE: Ventricular fibrillation (VF) in coronary heart disease accounts for up to 70% of sudden cardiac death. We examined whether diltiazem N-oxide (DNO) has ischaemia-selective antiarrhythmic activity. EXPERIMENTAL APPROACH: Randomised and blinded experiments were performed in rat isolated hearts and in anaesthetised rats to determine antiarrhythmic effectiveness, adverse drug reaction (ADR) profile and mechanism of action of DNO, using diltiazem as a positive control. The ratio of the lowest concentration with antiarrhythmic activity to the highest concentration without ADRs was defined as the translational therapeutic index (TTI). KEY RESULTS: ) prevented ischaemia-induced VF in anaesthetised rats, with diltiazem causing AV block and bradycardia and DNO causing no ADRs. CONCLUSIONS AND IMPLICATIONS: DNO was converted to diltiazem selectively in ischaemic cardiac tissue where it mimicked diltiazem's effect on VF, but without its associated ADRs. Neither drug affected cardiac energetics.
Hesketh et al. (Sun,) studied this question.