Promising approach for the preclinical assessment of cardiac risks using left ventricular pressure-volume loop analyses in anesthetized monkeys

Negative lusitropic property of nifekalant identified using ventricular pressure-volume loop analyses in anesthetized monkeys

“…Isoflurane, which was used to maintain the animals under anesthetic conditions during the experiment, is known to exert negative inotropic activity [3, 13]. Isoflurane is also known to reduce calcium and potassium channel currents in voltage-clamped vascular muscle cells derived from the canine coronary artery, and these functions might cause vasodilatory conditions or enhanced sensitivity to I Kr blocking action by nifekalant [6]; however, the administration of the vehicle control, 0.9% physiological saline, did not induce any significant changes in this isoflurane-anesthetized monkey as previously reported [16]. To the best of our knowledge, ours is the first in vivo study using non-rodents where nifekalant was evaluated using load-independent inotropic parameters.…”

“…These findings suggested that nifekalant had no detectable inotropic activity at the therapeutic plasma concentrations tested in which QT/QTc prolongation was observed, as was the case with the concentrations used in the canine treated with nifekalant [12, 17, 25]. Potassium channel inhibition alone probably had no effects on cardiac inotropy, although it might have had a neutralizing potential against positive inotropy by indirectly modulating the intracellular Ca 2+ concentration by maintaining intracellular K + concentration during cardiac repolarization [16]. Although the drug decreased the absolute value of the left ventricle relaxation velocity, LVdP/dt min and prolonged the time constant for isovolumic relaxation, tau, which is the gold standard for the LV relaxation velocity.…”

“…LV pressure-volume (PV) loop studies in the isoflurane-anesthetized monkey showed milrinone- and metoprolol-induced effects on cardiac inotropy and lusitropy, respectively [16]. Furthermore, dl -sotalol did not show any inotropic activity in the monkey PV loop analysis [16] because of its inhibitory effects on I Kr and β-blocking activity [1, 2], suggesting the practical utility of the LV PV loop method to evaluate the cardiac inotropic or lusitropic potential of drug candidates at the pre-clinical stage.…”

“…In the present study, the effects of potassium channel inhibition on multiple cardiohemodynamic and electrophysiological properties including cardiac inotropy/lusitropy of nifekalant, a representative I Kr blocker, was investigated using the LV PV-loop method in cynomolgus monkeys, which is an important animal used in non-clinical toxicological studies and in evaluation of pharmacological safety [19, 30]. Since the significance of non-clinical assessment for drug-induced alterations in cardiovascular functions using non-human primates as well as dogs are increasing, especially in drugs possibly targeting for susceptible patients [5, 11], we selected cynomolgus monkeys because of available background data using PV loop method for representative inotropic/lusitropic drugs in this species [15, 16].…”

Trastuzumab-induced negative chronotropic and lusitropic effects in cynomolgus monkeys

“…10 In addition, administration of the vehicle (0.9% physiological saline) did not affect any cardiovascular parameter over time before and after administration. 10 Therefore, the use of this model may adequately assess the fluctuation of cardiac electrophysiological or hemodynamic parameter of the test articles of interest at each measurement day. On the other hand, there are no FIGURE 2.…”