Assessment of the pharmacological effects of inotropic drugs on left ventricular pressure and contractility: an evaluation of the QA interval as an indirect indicator of cardiac inotropism.
BACKGROUND
The ICH S7A and S7B guidelines require that effects of test substances on the cardiovascular system be assessed with respect to blood pressure, heart rate and electrocardiogram intervals. Where adverse effects are identified additional supplemental studies, including ventricular contractility, should be conducted as deemed appropriate. However, there is an absence of definitive guidance regarding when to pursue supplementary studies, in part due to ill-defined criteria of what constitutes an adverse effect and to surgical/technical monitoring limitations of study designs. However with advances in technology it is now feasible to develop models for assessing LVP and contractility in conjunction with standard assessments. The objectives of this study were to 1) develop a model for chronic evaluation of LVP and contractility, 2) illustrate changes in LV contractility without concurrent proportional changes in heart rate and/or systemic blood pressure and 3) determine if the QA interval, the time between the Q on the ECG and the beginning of the upstroke on the arterial blood pressure, can be used as a indicator of altered LV contractility.


METHODS
Dogs (N=4) were implanted with a telemetry transmitter. LVP, contractility, ECG and BP were assessed prior to and up to 24 h following administration of Atenolol (10 mg/kg) and Pimobendan (0.45 mg/kg).


RESULTS
Atenolol caused an approximately 30% decrease in HR, followed by a sustained decrease in maximum left ventricular contractility (+dP/dt mmHg/s). No effects were noted on blood pressure. Pimobendan caused a 100% increase in contractility (+dP/dt mmHg/s) which remained elevated for approximately 4 h. No effects were noted on blood pressure. Heart rate was highly variable initial decreasing, followed by a highly variable increase until 4 h postdose. Following administration of both compounds changes in maximum left ventricular contractility correlated with reverse changes in QA interval duration.


CONCLUSIONS
This model demonstrates that evaluation of LV contractility complements measurements of heart rate and blood pressure as part of a more complete cardiovascular safety assessment strategy. Furthermore, we demonstrate an apparent correlation between dP/dt and QA interval and concluded that QA interval can be utilized as an indicator of a potential inotropic effect. However further confirmation should be assessed through additional in-vivo measurements of LVP and contractility.
Norton
K
K
Charles River Laboratories Preclinical Services, Montreal, Quebec, Canada. Kevin.norton@crl.com
Iacono
G
G
Vezina
M
M
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D001262:Atenolol / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D008297:Male; D023421:Models, Animal; D009200:Myocardial Contraction / Q000187:drug effects*; D011724:Pyridazines / Q000494:pharmacology*; D016277:Ventricular Function, Left / Q000187:drug effects*
D000319:Adrenergic beta-Antagonists; D002316:Cardiotonic Agents; D011724:Pyridazines; C041648:pimobendan; D001262:Atenolol