title: The effects of extracellular ions on beta-blocker cardiotoxicity.
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.
authors.affiliation: Department of Emergency Medicine, Division of Toxicology, Carolinas Medical Center, Charlotte, North Carolina 28232-2861, USA.
authors.forename: W
authors.initials: W
authors.lastname: Kerns
authors.forename: M
authors.initials: M
authors.lastname: Ransom
authors.forename: C
authors.initials: C
authors.lastname: Tomaszewski
authors.forename: J
authors.initials: J
authors.lastname: Kline
authors.forename: R
authors.initials: R
authors.lastname: Raymond
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000633:toxicity*; D000818:Animals; D001262:Atenolol / Q000633:toxicity; D003326:Coronary Circulation / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D006331:Heart Diseases / Q000139:chemically induced* / Q000188:drug therapy; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D011188:Potassium / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology; D011433:Propranolol / Q000633:toxicity; D051381:Rats; D012964:Sodium / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D017725:Ventricular Pressure / Q000187:drug effects
chemical_list: D000319:Adrenergic beta-Antagonists; D015221:Potassium Channels; D001262:Atenolol; D012964:Sodium; D011433:Propranolol; D011188:Potassium