Isolated perfused and paced guinea pig heart to test for drug-induced changes of the QT interval.
BACKGROUND
One of the biomarkers for assessing the risk of a cardiac adverse event is drug-induced prolongation of the QT interval. A model is needed for evaluating the potential liability of test compounds on QT interval in vitro. Since QT intervals can be generated from paced or spontaneously beating hearts, data so generated can also be used for validating QT(c) correction equations.


METHODS
Isolated guinea pig hearts were perfused in Locke's solution according to the Langendorff method. QT intervals were routinely measured from Lead II ECG waveforms.


RESULTS
Compounds known to inhibit HERG channel, such as dofetilide, prolonged the QT interval in this model. (+/-)Bay K8644, a calcium channel activator, prolonged the QT interval, while verapamil, a calcium channel blocker, shortened it. Procainamide, a sodium channel blocker, also prolonged the QT interval. Many of the compounds, which prolonged the QT interval, also prolonged PR interval, suggesting dual inhibition of the Ikr channel, the rapid component of delayed rectifier potassium channel, and the calcium channel. The QT/RR intervals exhibited a curvilinear relationship, which could be corrected into nearly straight horizontal lines by using correction equations derived from linear, parabolic, and hyperbolic models. However, these correction equations yielded different results on the QT prolongation produced by sotalol, which also slowed down the heart rate. With the data set obtained in this investigation, correction equations derived from linear and parabolic models worked better than the equations derived from the hyperbolic model. The exponential model did not fit at all.


CONCLUSIONS
QT intervals obtained under paced conditions provide the most direct and reliable QT information for a drug. The isolated perfused and paced guinea pig heart is a convenient model for studying the effect of compounds on QT interval in vitro.
Cheng
Hsien C
HC
Safety Pharmacology, Drug Safety Evaluation, Sanofi-Aventis, Bridgewater, NJ 08807, USA. hsien.cheng@sanofi-aventis.com
Incardona
Josephine
J
McCullough
Bruce
B
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000009:adverse effects; D000818:Animals; D002120:Calcium Channel Agonists / Q000009:adverse effects; D020117:Cisapride / Q000009:adverse effects; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D066298:In Vitro Techniques; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology; D008297:Male; D010477:Perfusion; D026902:Potassium Channel Blockers / Q000009:adverse effects; D011342:Procainamide / Q000009:adverse effects; D026941:Sodium Channel Blockers / Q000009:adverse effects
D002120:Calcium Channel Agonists; D051638:Ether-A-Go-Go Potassium Channels; D026902:Potassium Channel Blockers; D026941:Sodium Channel Blockers; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D011342:Procainamide; D020117:Cisapride