Ruthenium red-induced transition from ventricular fibrillation to tachycardia in isolated rat hearts: possible involvement of changes in mitochondrial calcium uptake.
BACKGROUND
Ventricular tachycardia (VT) is considered to be the most common precursor of ventricular fibrillation (VF) and sudden cardiac death. However, the mechanisms underlying the transition from VT to VF remain unclear despite more than a century of study. Here, we investigated whether perfusion of the heart with blockers of mitochondrial Ca(2+) uniporter changed the macrodynamics of the heart between VT and VF.


METHODS
The experiments were performed using Langendorff perfused isolated rat hearts in which left ventricular pressure (LVP) and left ventricular cardiomyogram (LVCMG) were measured. Sustained VT or VF was induced by burst pacing of the left ventricular muscles.


RESULTS
During pacing-induced sustained VF, perfusion of the heart with ruthenium red (RR) or Ru 360, blockers of mitochondrial Ca(2+) uniporter, resulted in the reversible conversion of VF to VT. In contrast, during pacing-induced sustained VT, perfusion of the heart with spermine, an activator of mitochondrial Ca(2+) uptake, resulted in the reversible conversion of VT to VF, and the effect was antagonized by cotreatment with RR. In addition, RR-induced conversion of VF to VT was antagonized by cotreatment with S(-)-Bay K8644 (Bay K), an activator of L-type Ca(2+) channels, suggesting that the inactivation of L-type Ca(2+) channels was responsible for the RR-induced effect on the macrodynamics of hearts. In fact, perfusion with verapamil, an antagonist of L-type Ca(2+) channels, during pacing-induced sustained VF, resulted in the conversion of VF to VT.


CONCLUSIONS
This study demonstrated that perfusion of isolated rat hearts with blockers of Ca(2+) uptake by mitochondria resulted in the reversible conversion of pacing-induced sustained VF to VT, suggesting that changes in mitochondrial Ca(2+) uptake were possibly involved in the transition between VT and VF.
Kawahara
Koichi
K
Laboratory of Biomedical Control, Research Institute for Electronic Science, Hokkaido University, Sapporo 060-0812, Japan. kawahara@bmc.es.hokudai.ac.jp
Takase
Marei
M
Yamauchi
Yoshiko
Y
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004195:Disease Models, Animal; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012430:Ruthenium Red / Q000494:pharmacology*; D013610:Tachycardia / Q000503:physiopathology*; D014693:Ventricular Fibrillation / Q000188:drug therapy / Q000503:physiopathology*; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D012430:Ruthenium Red; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D014700:Verapamil; D002118:Calcium