Antiarrhythmic effects of Na+/H+ exchange inhibitors

Cariporide, HOE-642 (4-isopropyl-3-methylsulphonylbenzoylguanidine methanes ulphonate), a novel Na+/H+ exchange (NHE) subtype 1 inhibitor, has antiarrh ythmic effects on coronary occlusion/reperfusion-induced arrhythmias in bot h 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 administere d after induction of coronary ischaemia or when the drug was administered s imultaneously with reperfusion. The favourable antiarrhythmic effects durin g ischaemia/reperfusion occurred without changes in the blood pressure, hea rt rate or ECG parameters. Cariporide showed antifibrillatory effects on co ronary artery occlusion/reperfusion-induced ventricular fibrillation in bot h rats and dogs although it did not show antiarrhythmic effect on ischaemia -induced ventricular arrhythmias. Another NHE inhibitor KB-R9032, (N-(4-iso propyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyI)guani dine methanesulfonate) had antiarrhythmic and antifibrillatory effects simi lar to cariporide both in dogs and rats, and furthermore it suppressed isch aemia-induced ventricular arrhythmias. Neither drug had deleterious effects on the heart rate and blood pressure, or on the ECG parameters in dogs. Su ch antiarrhythmic and antifibrillatory effects are specific for myocardial ischaemia-related arrhythmias. We showed that NHE inhibitors in dogs did no t have antiarrhythmic effects on digitalis- or adrenaline-induced arrhythmi as, the mechanisms of which are thought to be due to intracellular Ca2+ ove rload (produced by mechanisms other than NHE inhibition). The antiarrhythmi c 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 fo r treating or preventing arrhythmias in patients with coronary artery disea ses.