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Protective activity of calcium entry blockers against ouabain intoxication in anesthetized guinea pigs
Abstract:
Several studies have suggested a central role for calcium in the pathogenesis of digitalis-induced arrhythmias. To test this hypothesis, the effects on ouabain-induced arrhythmia of intraarterial pretreatment with the calcium entry blockers nifedipine, flunarizine, verapamil, diltiazem, and bepridil, the calcium entry promotor Bay K 8644, and CaCl2 were compared with those of the currently applied digitalis antidotes phenytoin and lidocaine in urethane-anesthetized (1.5 g/kg i.p.) guinea pigs. Pretreatment with nifedipine (0.03 and 0.1 mg/kg), flunarizine (1 and 3 mg/kg), and phenytoin (10 mg/kg) doubled the time (from 10-20 to 20-40 min) required to provoke toxic ECG changes. Verapamil, diltiazem, and bepridil caused a slight but significant reduction of ouabain toxicity. Pretreatment with CaCl2 (10 mg/kg) enhanced all toxic effects of ouabain. None of the above-mentioned pretreatments as such changed the ECG parameters. Bay k 8644 (0.03 and 0.1 mg/kg) enhanced the effects of ouabain on ventricular rhythm, but abolished the ouabain-induced impairment of AV conduction. Bay k 8644 as such increased heart rate (from 318 +/- 11 to 376 +/- 6 beats/min at 0.1 mg/kg) and shortened the PR interval. The negative inotropic effects of the calcium entry blockers were quantified in electrically paced (3 Hz) guinea pig isolated left atria 15 min after pretreatment with ouabain (3 X 10(-7) M). The rank order of potency for the negative inotropic effect was nifedipine greater than verapamil greater than bepridil greater than diltiazem greater than flunarizine. In conclusion, nifedipine, flunarizine, and phenytoin showed obvious and equally effective protection against ouabain-induced arrhythmia.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Calcium entry blockers like nifedipine and flunarizine, along with phenytoin, effectively protected against digitalis-induced arrhythmias in guinea pigs. These findings support calcium
Area of Science:
- Cardiovascular Pharmacology
- Cardiac Electrophysiology
Background:
- Digitalis glycosides, like ouabain, can induce arrhythmias.
- Calcium influx is implicated in the pathogenesis of these digitalis-induced arrhythmias.
Purpose of the Study:
- To investigate the protective effects of calcium entry blockers and other agents against ouabain-induced arrhythmias.
- To compare the efficacy of calcium modulators with established digitalis antidotes.
Main Methods:
- Ouabain-induced arrhythmias were studied in anesthetized guinea pigs.
- Pretreatment with calcium entry blockers (nifedipine, flunarizine, verapamil, diltiazem, bepridil), calcium promotor (Bay K 8644), CaCl2, phenytoin, and lidocaine was administered.
- Electrocardiogram (ECG) parameters and negative inotropic effects on isolated left atria were assessed.
Main Results:
- Nifedipine, flunarizine, and phenytoin significantly prolonged the time to toxic ECG changes, showing comparable protective effects.
- Verapamil, diltiazem, and bepridil offered moderate protection against ouabain toxicity.
- CaCl2 exacerbated ouabain's toxic effects, while Bay K 8644 modulated ventricular rhythm and AV conduction.
- The potency order for negative inotropic effects was nifedipine > verapamil > bepridil > diltiazem > flunarizine.
Conclusions:
- Nifedipine, flunarizine, and phenytoin demonstrate significant and comparable efficacy in preventing ouabain-induced arrhythmias.
- These findings reinforce the critical role of calcium in digitalis cardiotoxicity.
- Calcium entry blockers represent a promising therapeutic strategy for managing digitalis toxicity.