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The effects of extracellular ions on beta-blocker cardiotoxicity
W Kerns1, M Ransom, C Tomaszewski
1Department of Emergency Medicine, Division of Toxicology, Carolinas Medical Center, Charlotte, North Carolina 28232-2861, USA.
Abstract:
The mechanism of beta-blocker induced cardiotoxicity is poorly understood. One possible explanation is that beta-blockers induce ion dyshomeostasis, resulting in cardiac hyperpolarization. The intent of this study was to determine if modifying extracellular ions would reverse cardiotoxicity from two beta-blockers: propranolol (PROP) and atenolol (ATEN). Two treatments were studied: low extracellular K+ and high extracellular Na+. Isolated rat hearts were perfused on a Langendorff apparatus with Krebs-Henseleit- Bicarbonate buffer (KHB) solution. Toxicity (Tox) was induced by perfusing hearts for 30 min with KHB + PROP [5 microgram/ml] or KHB + ATEN [2.5 mg/ml]. Subsequently, hearts were perfused with KHB containing either PROP or ATEN, but modified by lowering K+ [2.3 mM] or raising Na+ [160 mM] for a 30-min treatment (Tx) period. Hearts were paced near the end of treatment. Cardiodynamics were monitored via a balloon-tipped catheter in the left ventricle. The first derivative of LV pressure (dP/dt) with respect to time served as our index of myocardial performance. Tx groups were as follows: (1) KHB only, (2) PROP only, (3) PROP + K, (4) PROP + Na, (5) ATEN only, (6) ATEN 4 K, and (7) ATEN + Na. PROP induced negative chronotropic effects and rendered the hearts refractory to pacing. ATEN demonstrated similar chronotropic toxicity plus decreased myocardial contractility. Tx with low extracellular K+ and high extracellular Na+ increased HR and restored the ability to pace, thereby reversing toxicity. These data suggest that beta-blocker toxicity is mediated via hyperpolarization.
Insights
Beta-blocker cardiotoxicity may stem from ion imbalances. Modifying extracellular potassium and sodium levels reversed toxicity in isolated rat hearts, suggesting hyperpolarization as the underlying mechanism.
Area of Science:
- Cardiology
- Pharmacology
- Ion Channel Physiology
Background:
- The mechanism of beta-blocker induced cardiotoxicity remains unclear.
- A leading hypothesis suggests beta-blockers cause ion dyshomeostasis, leading to cardiac hyperpolarization.
Purpose of the Study:
- To investigate if altering extracellular ion concentrations can reverse beta-blocker cardiotoxicity.
- Specifically examined the effects of low extracellular potassium (K+) and high extracellular sodium (Na+) on propranolol (PROP) and atenolol (ATEN) induced toxicity.
Main Methods:
- Isolated rat hearts were perfused using a Langendorff apparatus.
- Cardiotoxicity was induced with PROP or ATEN.
- Toxicity was then treated by modifying the perfusate with low K+ or high Na+; cardiodynamics (dP/dt) were monitored.
Main Results:
- Propranolol induced negative chronotropic effects and refractoriness to pacing.
- Atenolol caused similar chronotropic toxicity and reduced myocardial contractility.
- Treatment with low K+ and high Na+ restored heart rate and pacing ability, reversing toxicity.
Conclusions:
- Beta-blocker induced cardiotoxicity appears to be mediated by cardiac hyperpolarization.
- Modulating extracellular ion concentrations offers a potential strategy to counteract beta-blocker toxicity.