The Effects of Extracellular Ions on β-Blocker Cardiotoxicity

• Published in: Toxicology and applied pharmacology 1996-03, Vol.137 (1), p.1-7
• Main Authors: Kerns II, William, Ransom, Mary, Tomaszewski, Christian, Kline, Jeffrey, Raymond, Richard
• Format: Article
• Language: English
• Subjects: Adrenergic beta-Antagonists - toxicity; Animals; Atenolol - toxicity; Biological and medical sciences; Coronary Circulation - drug effects; Drug toxicity and drugs side effects treatment; Heart - drug effects; Heart Diseases - chemically induced; Heart Diseases - drug therapy; Heart Rate - drug effects; Male; Medical sciences; Pharmacology. Drug treatments; Potassium - chemistry; Potassium - metabolism; Potassium - pharmacology; Potassium Channels - drug effects; Potassium Channels - physiology; Propranolol - toxicity; Rats; Sodium - chemistry; Sodium - metabolism; Sodium - pharmacology; Toxicity: cardiovascular system; Ventricular Pressure - drug effects
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1006/taap.1996.0051

The mechanism of β-blocker induced cardiotoxicity is poorly understood. One possible explanation is that β-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 β-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 μg/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 + ↓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 β-blocker toxicity is mediated via hyperpolarization.