Protective action of cimetidine against ouabain-induced pressor effects, arrhythmias, and lethality in guinea pigs.
The effect of the H2-receptor antagonist cimetidine on ouabain cardiotoxicity was studied in anesthetized guinea pigs. Ouabain, infused intravenously at 3.0 micrograms X kg-1 X min-1, was lethal in a dose of 44.0 +/- 3.5 micrograms (n = 6). All control animals died in ventricular fibrillation. Cimetidine, infused concurrently at 10, 30, and 100 micrograms X kg-1 X min-1, significantly increased the lethal dose of ouabain and delayed the onset of various arrhythmias and fibrillation. Cimetidine abolished ouabain-induced pressor effects that have been reported to be neurally mediated; the course of heart-rate changes in ouabain-treated animals, however, was unaffected by cimetidine. In vitro, cimetidine had no effect on the inotropic action of ouabain at concentrations as high as 10(-4) M, whereas serum levels of cimetidine in protected animals did not exceed this concentration. When the ouabain infusion rate was reduced by 50% (to 1.5 microgram X kg-1 X min-1), the lethal dose increased to 72.7 +/- 4.7 micrograms (n = 6), the predominant mode of death changed from fibrillation to cardiac standstill, ouabain-induced pressor effects were absent, and cimetidine no longer exhibited a protective action. Taken together, these findings support the hypothesis that cimetidine acts primarily against indirect components of digitalis toxicity, and so may be potentially valuable for increasing the margin of safety of the cardiac glycosides.
J P
JP
Trzeciakowski
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000517:prevention & control*; D001794:Blood Pressure / Q000187:drug effects*; D002927:Cimetidine / Q000097:blood / Q000494:pharmacology*; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D010042:Ouabain / Q000037:antagonists & inhibitors* / Q000633:toxicity
D010042:Ouabain; D002927:Cimetidine