The value added by measuring myocardial contractility 'in vivo' in safety pharmacological profiling of drug candidates.
BACKGROUND
The objective of this study was to define the normal LVdP/dt (an index of myocardial contractility)-heart rate relationship in telemetered conscious dogs, primates and mini-pigs in our laboratory and to use these data as the basis for an additional parameter useful in drug safety evaluation.


METHODS
Trained dogs, Rhesus monkeys, Cynomolgus monkeys and mini-pigs (Goettinger) were equipped with radiotelemetry transmitters (ITS). Aortic pressure (AP), left ventricular pressure (LVP), a lead II ECG and body temperature could be continuously monitored. The contractility index LVdP/dtmax was derived from the LVP signal. Notocord HEM 4.1 software was used for data acquisition. For each species an LVdP/dt-heart rate relationship was evaluated using spontaneous heart rates (HR) throughout the observation period. A validation compound with positive inotropic effects (pimobendan) was then used to investigate the LVdP/dt-heart rate relationship.


RESULTS
There was a clear LVdP/dt-HR relationship in the animals tested. The inotropic agent pimobendan demonstrated the expected shift in this relationship.


CONCLUSIONS
Contractility of the myocardium is regulated by autonomic input activating primarily myocardial beta1-adrenoceptors, but it is also affected by the "force-frequency" relationship. Compounds can therefore either directly or indirectly affect the contractility of the heart. The chronotropic effects are routinely measured in preclinical studies; however, the inotropic effects are not routinely analysed in cardiovascular safety studies. Our experience strongly recommends including this evaluation for drug candidate selection. The evaluation of LVdP/dtmax, as an index of myocardial contractile state must, however, take into account its HR-dependency.
Markert
Michael
M
Department of Drug Discovery Support, General Pharmacology Group, Boehringer Ingelheim Pharma GmbH & Co KG, J91 UG, Birkendorferstr.65, 88397 Biberach, Germany. Michael.markert@bc.boehringer-ingelheim.com
Klumpp
Anja
A
Trautmann
Thomas
T
Mayer
Karin
K
Stubhan
Miriam
M
Guth
Brian
B
D000284:Administration, Oral; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology; D004285:Dogs; D004353:Drug Evaluation, Preclinical / Q000295:instrumentation / Q000379:methods; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D011724:Pyridazines / Q000008:administration & dosage / Q000494:pharmacology; D015203:Reproducibility of Results; D012815:Signal Processing, Computer-Assisted; D013045:Species Specificity; D013552:Swine; D013556:Swine, Miniature; D013686:Telemetry / Q000295:instrumentation / Q000379:methods*; D016277:Ventricular Function, Left / Q000187:drug effects
D002316:Cardiotonic Agents; D011724:Pyridazines; C041648:pimobendan