Effects of proton buffering and of amiloride derivatives on reperfusion arrhythmias in isolated rat hearts. Possible evidence for an arrhythmogenic role of Na(+)-H+ exchange.
We investigated the hypothesis that an accelerated Na+o-H+i exchange on reperfusion may lead to a displacement of the 3[Na+] [Ca2+]i/o equilibrium in favor of an arrhythmogenic rise in cytosolic [Ca2+]. Supporting evidence was obtained by subjection of isolated rat hearts to 15 minutes of low-flow (5% of control) ischemia and 2 minutes of reperfusion in the presence of a Krebs-Henseleit HEPES buffer (pH 7.4) containing lactate (10 mM). At first, the [HEPES] was fixed at 5 mM; then, 2 minutes before reflow, either the [HEPES] was varied from 50 to 1 mM to slow H+o washout, or increasing concentrations of 5-(N,N-dimethyl)-amiloride (Ki 7 microM) or 5-(N,N-hexamethylene)-amiloride (Ki 0.2 microM) were added for inhibition of Na(+)-H+ exchange. In each case, reperfusion ventricular arrhythmias were reduced by 69-73% (p less than 0.001).
Dennis
S C
SC
Medical Research Council Ischemic Heart Disease, University of Cape Town Medical School, South Africa.
Coetzee
W A
WA
Cragoe
E J
EJ
Opie
L H
LH
D000584:Amiloride / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology*; D002021:Buffers; D002352:Carrier Proteins / Q000502:physiology*; D006531:HEPES / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D015428:Myocardial Reperfusion Injury; D010879:Piperazines / Q000494:pharmacology*; D011522:Protons; D051381:Rats; D011919:Rats, Inbred Strains; D017923:Sodium-Hydrogen Exchangers
D002021:Buffers; D002352:Carrier Proteins; D010879:Piperazines; D011522:Protons; D017923:Sodium-Hydrogen Exchangers; C057360:5-(N,N-hexamethylene)amiloride; D000584:Amiloride; D006531:HEPES