Clinical and in vivo antiarrhythmic potential of sodium-hydrogen exchange inhibitors.
Intracellular acidification may be the initial stimulus for a cascade of events contributing to intracellular calcium overload. Ischaemia results in the accumulation of lactate and other proton donors causing intracellular acidification. During reperfusion the activity of the Na+/H+ exchanger recovers, allowing extrusion of protons at the expense of increases in intracellular sodium. The rise in intracellular sodium decreases the gradient required for sodium calcium exchange, resulting in accumulation of intracellular calcium. These data are in keeping with the pathophysiological model that the Na+/H+ exchanger is an important part of a cascade leading from intracellular acidosis to intracellular sodium loading followed by calcium overload. From this model we predicted that amiloride would be antiarrhythmic. In 1988, we reported that low concentration of amiloride (0.1-0.3 microM) suppresses the induction of sustained ventricular tachyarrhythmias in dogs late following infarction. Amiloride suppressed inducible ventricular tachycardia in approximately 50% of the animals. In an extension of this work we assessed the efficacy of amiloride in suppressing inducible ventricular tachycardia in humans who presented with symptomatic ventricular tachycardia. In that study, amiloride manifested antiarrhythmic activity, but not to the degree that was observed in our dog model. Six of 31 patients (19%) had complete suppression of induced ventricular tachycardia. In an extension of this work, we assessed in our in vivo dog model which of the pharmacological effects of amiloride were associated with antiarrhythmic efficacy.(ABSTRACT TRUNCATED AT 250 WORDS)
Duff
H J
HJ
Cardiovascular Research Group, University of Calgary, Alberta, Canada.
D000584:Amiloride / Q000627:therapeutic use*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy*; D004285:Dogs; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*
D017923:Sodium-Hydrogen Exchangers; D000584:Amiloride