The positive inotropic drugs DPI 201-106, BDF 9148, and veratridine increase ouabain toxicity and [3H]ouabain binding in guinea pig heart.
The interaction of three positive inotropic compounds, which are modulators of sodium channels, with the cardiac glycoside ouabain was investigated in isolated guinea pig atria. In the presence of DPI 201-106 (3 x 10(-7) M), of its new acetidine derivative BDF 9148 (10(-7) M), or of veratridine (10(-6) M), the threshold ouabain concentration to induce toxicity was lowered by a factor of 2. This effect can be explained by the observation that specific equilibrium [3H]ouabain binding in intact atria was elevated by these compounds in the appropriate concentrations. The binding results were analyzed by means of a previously established model of "positive cooperative ouabain binding to intact myocardium," which describes the relationship between cellular sodium homeostasis and ouabain binding. The extent to which the compounds increased ouabain binding was in good quantitative agreement with the observed shift in the threshold concentration of ouabain toxicity. The increase of specific [3H]ouabain binding is likely initiated by a gain in cytosolic sodium. It takes place at the cellular level only, since a direct enhancement of [3H]ouabain binding to isolated cardiac membranes was not found. In conclusion, at least under some conditions, new inotropic drugs acting as sodium channel modulators can increase the risk of digitalis toxicity.
Herzig
S
S
Department of Pharmacology, University Kiel, F.R.G.
Lilienthal
E
E
Mohr
K
K
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004074:Digitoxin / Q000633:toxicity; D004357:Drug Synergism; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism; D010042:Ouabain / Q000378:metabolism / Q000633:toxicity*; D010879:Piperazines / Q000494:pharmacology*; D014701:Veratridine / Q000494:pharmacology*
D002316:Cardiotonic Agents; D010879:Piperazines; D010042:Ouabain; D014701:Veratridine; C046261:DPI 201-106; D004074:Digitoxin