Digitalis cardiotoxicity: cellular calcium overload a possible mechanism.
Isolated perfused guinea pig (Langendorff) heart was employed to determine if the myocardial mechanical dysfunction (mechanical toxicity) produced by toxic concentration of ouabain (1 microM) was accompanied by alterations in mitochondrial function. Ouabain (1 microM) produces a transient increase in the myocardial contractile force and then a continuous decline in the left ventricular mechanical function. Mitochondria isolated from ouabain perfused hearts showed a significantly higher rate of 45Ca2+ uptake and reduction in oxidative phosphorylation. The rate of ATP generation was reduced by almost 50% at the time of contracture development. Verapamil or nifedipine, when combined with ouabain in the perfusion medium, delayed or abolished the mechanical toxicity in a dose dependent manner. The mitochondria isolated from these hearts demonstrated normal rate of Ca2+ uptake and ATP generation capacity. The data indicate that the cardiac mechanical dysfunction induced by toxic doses of ouabain may be associated with mitochondrial Ca2+ overload and dysfunction and that the Ca2+ channel blockers may have a protective effect.
Khatter
J C
JC
Department of Medicine, University of Manitoba, Winnipeg, Canada.
Agbanyo
M
M
Navaratnam
S
S
Nero
B
B
Hoeschen
R J
RJ
D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000502:physiology; D004071:Digitalis Glycosides / Q000633:toxicity*; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D008297:Male; D008929:Mitochondria, Heart / Q000378:metabolism / Q000502:physiology; D010042:Ouabain / Q000633:toxicity; D010477:Perfusion; D012964:Sodium / Q000502:physiology
D004071:Digitalis Glycosides; D010042:Ouabain; D012964:Sodium; D002118:Calcium