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Effects of BAY K-8644 on inotropic and arrhythmogenic actions of digoxin
Abstract:
Myocardial intracellular 'Ca2+ overload' may be involved in the direct arrhythmogenic actions of cardiotonic steroids. This proposal was examined by determining if the sensitivity of guinea-pig atrial muscle to digoxin-induced arrhythmias was affected by BAY K-8644, a 1,4-dihydropyridine derivative which promotes Ca2+ influx via slow channels. BAY K-8644 significantly reduced both the time required for a given concentration of digoxin to produce arrhythmias and the amount of digoxin bound to atrial muscle at the onset of arrhythmias. In addition, BAY K-8644 increased the maximum developed tension observed in the presence of digoxin before the onset of arrhythmias. Similar results were obtained with increasing concentrations of buffer Ca2+. In contrast, A23187, a Ca2+ ionophore, enhanced the sensitivity to digoxin-induced arrhythmias without affecting maximum developed tension. These results suggest that increases in intracellular Ca2+ enhance cardiac sensitivity to digoxin-induced arrhythmias and that the arrhythmogenic action may involve Ca2+ overload at a pool other than that which activates contractile proteins.
Insights
Increased intracellular calcium enhances cardiac sensitivity to digoxin-induced arrhythmias. This suggests calcium overload, not contractile protein activation, may drive these dangerous heart rhythms.
Area of Science:
- Cardiology
- Pharmacology
- Molecular Biology
Background:
- Cardiotonic steroids, like digoxin, can cause arrhythmias.
- Myocardial intracellular calcium overload is a potential mechanism for these arrhythmias.
Purpose of the Study:
- To investigate if enhanced calcium influx affects sensitivity to digoxin-induced arrhythmias.
- To determine the role of intracellular calcium in digoxin's arrhythmogenic actions.
Main Methods:
- Utilized guinea-pig atrial muscle preparations.
- Administered digoxin with and without BAY K-8644 (calcium channel activator) or A23187 (calcium ionophore).
- Measured time to arrhythmia onset, digoxin binding, and developed tension.
Main Results:
- BAY K-8644 reduced time to digoxin-induced arrhythmias and digoxin binding.
- BAY K-8644 increased developed tension in the presence of digoxin.
- Increased buffer calcium mimicked BAY K-8644 effects.
- A23187 enhanced arrhythmia sensitivity without altering tension.
Conclusions:
- Elevated intracellular calcium increases cardiac sensitivity to digoxin-induced arrhythmias.
- The arrhythmogenic mechanism may involve calcium overload in a non-contractile protein pool.