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ToxSci Advance Access published online on November 4, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg254
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received July 17, 2003; accepted September 16, 2003
© 2003 Society of Toxicology

Safety Assessment

QT and RR Intervals in Conscious and Anesthetized Guinea Pigs with Highly Varying RR Intervals and Given QTc-Lengthening Test Articles

Robert L. Hamlin 1*, Anusak Kijtawornrat 1, Bruce W. Keene 2, and David M. Hamlin 3

1 Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210
2 QTest Labs, Inc. 6456 Fiesta Drive, Columbus, OH 43235; North Carolina State University, Raleigh, North Carolina 27606
3 QTest Labs, Inc. 6456 Fiesta Drive, Columbus, OH 43235

* To whom correspondence should be addressed. E-mail: rhamlin{at}qtestlabs.com.


  Abstract

A facile system for obtaining electrocardiograms from conscious animals was used to conduct studies on 12 animals studied both conscious and anesthetized, on 4 conscious animals given vehicle (0.5% methylcellulose) and QT-lengthening test articles, and on 6 animals given test articles thought to not lengthen QTc. In 12 animals whose ECG's were monitored via a bipolar transthoracic ECG, heart rates were slowed with 1.0 mg/kg zatebradine, while they were conscious in their slings, and after being anesthetized with ketamine/xylazine.

The following regression equations were obtained relating QT to RR: QT=44.7lnRR-132.9, r2=0.7, for conscious animals, QT=79.4lnRR-287.4, r2=0.8 for anesthetized animals, with RR intervals varying between 150 and 550 ms. The anesthetic increases QT at all RR intervals (p<0.001), but does not change the slope of the relationship between QT and RR when compared with the conscious guinea pig. The Fridericia method was best for correcting QT for RR interval in conscious guinea pigs, but the Bazett method was best for correcting in anesthetized animals.

QTc lengthened significantly in all conscious guinea pigs given, orally, cisapride, ketoconazole and sotalol (positive test articles), and did not change with methylcellulose (the vehicle) or with propranolol, verapamil or enalapril (negative controls).

These techniques and relationships demonstrate that this methodology may be useful in exploring torsadogenic effects of novel pharmacological entities.

Key Words: guinea pig, QT, RR, QTc, anesthesia, conscious .


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