Antiarrhythmic effects of Na+/H+ exchange inhibitors

Cariporide, HOE-642 (4-isopropyl-3-methylsulphonylbenzoylguanidine methanesulphonate), a novel Na+/H+ exchange (NHE) subtype 1 inhibitor, has antiarrhythmic effects on coronary occlusion/reperfusion-induced arrhythmias in both in vitro and in vivo rat hearts, which might be induced by intracellular Ca2+ overload following myocardial ischaemia. These antiarrhythmic effects on reperfusion arrhythmias were observed even when the drug was administered after induction of coronary ischaemia or when the drug was administered simultaneously with reperfusion. The favourable antiarrhythmic effects during ischaemia/reperfusion occurred without changes in the blood pressure, heart rate or ECG parameters. Cariporide showed antifibrillatory effects on coronary artery occlusion/reperfusion-induced ventricular fibrillation in both rats and dogs although it did not show antiarrhythmic effect on ischaemia-induced ventricular arrhythmias. Another NHE inhibitor KB-R9032, (N-(4-isopropyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyI)guanidine methanesulfonate) had antiarrhythmic and antifibrillatory effects similar to cariporide both in dogs and rats, and furthermore it suppressed ischaemia-induced ventricular arrhythmias. Neither drug had deleterious effects on the heart rate and blood pressure, or on the ECG parameters in dogs. Such antiarrhythmic and antifibrillatory effects are specific for myocardial ischaemia-related arrhythmias. We showed that NHE inhibitors in dogs did not have antiarrhythmic effects on digitalis- or adrenaline-induced arrhythmias, the mechanisms of which are thought to be due to intracellular Ca2+ overload (produced by mechanisms other than NHE inhibition). The antiarrhythmic and antifibrillatory mechanism of NHE inhibitors may be a result of their NHE inhibition, as judged by the doses used, and they may become useful for treating or preventing arrhythmias in patients with coronary artery diseases.