Methods and limitations of an experimental model of long QT syndrome.
An experimental model of the long QT syndrome has been developed in conscious dogs. This report discusses the methods used in its preparation and the strengths and weaknesses of the model. This new model is suitable for screening the bradycardia-dependent proarrhythmic effects of drugs and for studying the electrophysiology of "torsades de pointes." Permanent bradycardia (RR: 1558 +/- 83 ms) was obtained in 37 dogs by chemically-induced complete atrioventricular block. A 10% further increase of ventricular repolarization (QT: 306 +/- 7.0 ms to 331 +/- 5.5 ms) was obtained in 28 of these dogs by diuretic-induced hypokalemia. Diuretics, despite saline replacement, induced some degree of functional renal failure and extracellular volume losses. The QT interval increased although ventricular cycle length decreased slightly. These biological and electrophysiological parameters were reproducible except for a slow increase in plasma creatinine. Cardiac failure and sudden death rarely occurred. The most severe, but reversible, renal failure occurred in some dogs given the highest diuretic doses. Hypokalemia resulted in ventricular arrhythmias in only 6 dogs, 2 of them exhibiting runs of ventricular tachycardia and even "torsade de pointes" as their potassium levels fell below 2 mmol/L. The results of studies with several drugs using the model, with or without hypokalemia, or with bradycardia worsened by propranolol are analysed.
Laboratoire de Pharmacologie (Faculté de Médecine Saint-Antoine-Université Pierre et Marie Curie), Paris, France.
J
J
Weissenburger
F
F
Chezalviel
J M
JM
Davy
P
P
Lainée
C
C
Guhennec
E
E
Penin
F
F
Engel
L
L
Cynober
G
G
Motté
G
G
Cheymol
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology; D001283:Atrioventricular Node / Q000502:physiology; D001581:Benzothiadiazines; D003404:Creatinine / Q000097:blood; D016206:Databases, Bibliographic; D004195:Disease Models, Animal; D004232:Diuretics; D004285:Dogs; D004562:Electrocardiography; D015716:Electrocardiography, Ambulatory; D004594:Electrophysiology; D005665:Furosemide / Q000494:pharmacology; D007008:Hypokalemia / Q000503:physiopathology; D008133:Long QT Syndrome / Q000503:physiopathology*; D011188:Potassium / Q000097:blood; D012964:Sodium / Q000097:blood; D049993:Sodium Chloride Symporter Inhibitors / Q000494:pharmacology; D016171:Torsades de Pointes / Q000503:physiopathology
D001581:Benzothiadiazines; D004232:Diuretics; D049993:Sodium Chloride Symporter Inhibitors; D005665:Furosemide; D012964:Sodium; D003404:Creatinine; D011188:Potassium