Modulation of the electrophysiological effects of ischemia reperfusion by methylisobutyl amiloride.
We studied the effect of the Na+/H+ exchanger inhibitor methylisobutyl amiloride (MIA, 1 microM) on action potential characteristics and arrhythmias induced by: (a) reperfusion following regional ischemia in rat hearts and (b) realkalization after lactate acidosis in rabbit hearts. We also determined the effect of MIA on the incidence of transient inward currents (ITIs) induced by acidosis-realkalization in rabbit cardiocytes. Ligation of the LAD coronary artery for 10 min depolarized the resting potential from -78 +/- 1.9 mV to -66.9 +/- 1.0 mV and depressed the action potential but did not induce overt arrhythmias. Delayed afterdepolarizations were observed during ischemia in 50% of untreated hearts whereas reperfusion produced severe ventricular tachyarrhythmias in all of them. MIA reduced the incidence of arrhythmias to 27% and their duration to less than 1 min. MIA increased action potential duration by 38 +/- 4.1%. BaCl2 produced a similar APD lengthening and had an antifibrillatory effect. Acidic reperfusion induced bradycardia and reduced severity of arrhythmias. In rabbit hearts, MIA increased the action potential duration by 61 +/- 4.3% and abolished arrhythmias on realkalization. Eleven out of 18 cells developed transient inward currents during acidosis-realkalization and seven of them underwent irreversible injury. MIA prevented the appearance of ITIs, had no effect on ICa,L but decreased the outward component of IK1 by 50%. Our results suggest that the protective effect of MIA is in part due to changes in cellular electrical activity that modulate Na+ and Ca2+ entry via different pathways.
Ruiz Petrich
E
E
Department of Physiology and Biophysics, Faculty of Medicine, University of Sherbrooke, QC Canada.
Ponce Zumino
A
A
Moffat
M P
MP
Rioux
Y
Y
Schanne
O F
OF
D000584:Amiloride / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism / Q000503:physiopathology*; D004594:Electrophysiology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology*; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors / Q000502:physiology
D017923:Sodium-Hydrogen Exchangers; D000584:Amiloride; C056369:5-(N-methyl-N-isobutyl)amiloride