The value added by measuring myocardial contractility ‘in vivo’ in safety pharmacological profiling of drug candidates

Introduction: 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. Discussion: Contractility of the myocardium is regulated by autonomic input activating primarily myocardial β1-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.