Tedisamil: master switch of nature?

Abstract

Decreasing heart rate is potentially useful in ischaemic heart disease. Tedisamil is a bradycardic agent resulting from its ability to inhibit transient outward current (I(to)) in atria. Tedisamil inhibits I(to), potassium current (IK), K(ATP) and the protein kinase A-activated chloride channel in ventricles as well as vascular IK and Ca(2+)-activated IK (IK((Ca))). Tedisamil prolongs cardiac action potentials and the corrected QT (QTc) of the ECG and also increases cardiac refractoriness. Tedisamil is anti-arrhythmic in animal models of ventricular arrhythmias and atrial flutter. The bradycardic effect of tedisamil is associated with a reduction in myocardial oxygen demand. On isolated rat ventricle, tedisamil is a positive inotrope and on isolated rabbit atria, tedisamil reverses the negative inotropic effect of pinacidil. Tedisamil contracts the isolated rat portal vein and aorta, reduces cromakalim-induced relaxations of contracted rat aorta and increases blood pressure in animals and humans. Tedisamil is 96% bound to plasma proteins, has a plasma half-life of about 10 h and is cleared from the kidney unchanged. Clinical trials have shown that the electrophysiology of tedisamil is that of a class III anti-arrhythmic. In coronary artery disease, tedisamil has no effect on inotropism and increases the threshold for angina. Potassium channel blockade with tedisamil may have advantages over calcium channel blockers or K(ATP) channel openers as an anti-ischaemic mechanism in coronary artery disease. In exercise-induced myocardial ischaemia, beta-blockers are probably favourable to tedisamil, as they will limit the increase in heart rate, contractility and blood pressure caused by sympathetic stimulation, whereas tedisamil will not. In heart failure patients, tedisamil reduces heart rate, but increases blood pressure. The usefulness of tedisamil as a bradycardic agent is limited by the increase in blood pressure. A drug that is bradycardic without increasing blood pressure would be an improvement on tedisamil as the master switch of nature for ischaemic heart disease.