QA interval as an indirect measure of cardiac contractility in the conscious telemeterised rat: model optimisation and evaluation.
BACKGROUND
Conscious telemeterised rats are used for early assessment of cardiovascular drug safety. This paper details the surgery required to allow key cardiovascular parameters to be determined and describes how QA interval (QAI), a surrogate measure of cardiac contractility, is related to a more direct measure of cardiac contractility, dP/dt(max) (LVdP/dt(max)). Experimental studies examining the effect of both positive and negative inotropes are described.


METHODS
Eight rats were surgically implanted with telemetry probes for measuring blood pressure, heart rate, activity, body temperature and ECG parameters. Initial studies focussed on evaluating surgical procedures aimed at improving the ECG signal to allow QAI quantification. Once achieved, experimental studies were undertaken with verapamil, salmeterol, milrinone or vehicle. Following treatment, data was collected for approximately 20 h from pair-housed animals to establish effects on QAI or LVdP/dt(max), which was measured directly from the left ventricle in a separate group of rats.


RESULTS
The modified ECG lead placement produced both a qualitative and quantitative improvement in ECGs. Increases in cardiac contractility (measured directly) were paralleled by a decrease in QAI (measured indirectly). Salmeterol and milrinone increased (all p<0.05) LVdP/dt(max) (1942+/-452 and 2333+/-506 mmHg/s, respectively) and decreased QAI (3.5+/-0.54 and 2.9+/-0.43 ms, respectively). In contrast, the negative inotrope verapamil decreased LVdP/dtmax (-2119+/-300 mmHg/s) and increased QAI (4.9+/-0.46 ms). A statistically significant (p<0.001) linear relationship was identified between log(10)(QAI) and log(10)(LVdP/dt(max)).


CONCLUSIONS
Improvements in ECG signal quality, resulting from refinements in surgical techniques allowed for the reliable quantification of ECG parameters. The linear relationship demonstrated between log(10)(QAI) and log(10)(LVdP/dt(max)) indicates that QAI may be a useful index of cardiac contractility in routine rat cardiovascular safety studies. These limited studies support the use of QAI as an indirect measure of cardiac contractility in the rat.
Adeyemi
O
O
Global Safety Pharmacology Department, Pfizer Global Research and Development, Sandwich, UK.
Roberts
S
S
Harris
J
J
West
H
H
Shome
S
S
Dewhurst
M
M
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D002317:Cardiovascular Agents / Q000494:pharmacology; D003243:Consciousness; D004353:Drug Evaluation, Preclinical / Q000295:instrumentation / Q000379:methods; D004562:Electrocardiography / Q000187:drug effects; D017408:Guidelines as Topic; D006339:Heart Rate / Q000187:drug effects*; D008297:Male; D023421:Models, Animal; D008955:Models, Cardiovascular; D009200:Myocardial Contraction / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013686:Telemetry / Q000295:instrumentation / Q000379:methods*; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects
D002317:Cardiovascular Agents