Synergism between UK 38485 and ICI 185282 against digoxin-induced arrhythmias in guinea-pigs.
In this study, the combination of a thromboxane synthetase inhibitor (UK 38485) and a thromboxane receptor antagonist (ICI 185282) was tested for an interaction of potential therapeutic importance and the effect of acetylsalicylic acid pretreatment on this combination was evaluated in digoxin-induced arrhythmias in guinea-pigs. Drug treatments at the dose combinations used (ICI 185282: 0.2 mg/kg + 0.2 mg/kg/hr + UK 38485 0.1 mg/kg/hr and ICI 185282: 2 mg/kg + 2 mg/kg/hr + UK 38485 1 mg/kg/hr) markedly reduced the incidence of ventricular fibrillation, mortality rate and arrhythmia score. Pretreatment with acetylsalicylic acid plus drug combination resulted in a dose-dependent increase in mortality rate and arrhythmia score. The increase in mean arterial blood pressure, observed after digoxin administration, was inhibited by the combination therapy. Although heart rate values were increased, the computed pressure-rate index remained unchanged when compared with the control group. These data suggest that the combined treatment with a thromboxane synthetase inhibitor and a thromboxane receptor antagonist provides a better protection against digoxin intoxication than with either agent alone. Furthermore, the results illustrate that formation of cyclooxygenase metabolites of arachidonic acid plays an important role in this action.
Kanzik
I
I
Department of Pharmacology, Faculty of Pharmacy, Gazi University, Ankara, Turkey.
Zengil
H
H
Ipek
N
N
Cakici
I
I
Abacioglu
N
N
Dörtlemez
H
H
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000188:drug therapy*; D001241:Aspirin / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D004077:Digoxin; D004146:Dioxanes / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004357:Drug Synergism; D005260:Female; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D014693:Ventricular Fibrillation / Q000517:prevention & control
D004146:Dioxanes; D007093:Imidazoles; C059061:ICI 185282; D016718:Arachidonic Acid; C039242:dazmegrel; D004077:Digoxin; D011451:Prostaglandin-Endoperoxide Synthases; D013930:Thromboxane-A Synthase; D001241:Aspirin