Digoxin cardiotoxicity in aging anesthetized F344 rats

Area of Science:

• Pharmacology
• Gerontology
• Cardiovascular Physiology

Background:

• Digitalis (cardiac glycoside) toxicity sensitivity increases with age.
• The specific pharmacokinetic and pharmacodynamic factors contributing to age-related digitalis sensitivity remain unclear.

Purpose of the Study:

• To investigate if aging affects digitalis tolerance in an animal model.
• To determine if altered cardiac or autonomic nervous system responsiveness mediates age-related changes in digitalis tolerance.

Main Methods:

• Male F344 rats of three age groups (4, 14, 25 months) received intravenous digoxin infusions.
• Two anesthetic regimens (AR1: age-adjusted urethane; AR2: alpha-chloralose plus urethane) were used.
• Continuous monitoring of heart rate, EKG, blood pressure, and baroreceptor reflex function was performed.

Main Results:

• Senescence significantly reduced the time to digoxin-induced atrioventricular (AV) dissociation in both anesthetic regimens.
• Under AR1, digoxin doses for ventricular extrasystoles and death were not age-dependent.
• Under AR2, older rats required higher digoxin doses for ventricular arrhythmias and cardiac arrest, unlike AR1.
• Serum digoxin levels at cardiac arrest did not differ significantly with age.

Conclusions:

• Aging in F344 rats promotes sensitivity to digoxin-induced AV dissociation via pharmacodynamic mechanisms.
• Aging does not appear to increase sensitivity to digoxin-induced ventricular arrhythmias or cardiac arrest in this model.
• Anesthetic regimen influences the observed age-related effects on digitalis toxicity.