e6 Meeting abstracts

EVALUATION OF IMIPRAMINE ON HEART: FROM IN VITRO (IKr, INa, AND APD) TO IN VIVO (TELEMETRY ECG)

Wenge Yu, Masakazu Imaizumi, Kazuaki Sasaki, Tatsumi Inui, Naoki Watanabe, Hiroshi Atai, Hiromi Iizuka, Katsuhide Nishi

Panapharm Laboratories Co., Ltd. Kumamoto, Japan

Introduction and methods: To clarify the ionic mechanism of cardiovascular side effects of imipramine, a tricyclicantidepressant, the following assays were applied: patch clamp study on IKr, which is encoded by human ether-a-go-go-relatedgene (hERG), and on the Na current of isolated guinea pig ventricular myocytes; action potential recording of isolated guineapig papillary muscles; and continuously recording of telemetry ECG of conscious and anesthetic beagle dogs. Results: 1.Imipramine inhibited hERG currents with IC50 value of 9.6 μmol/L. 2. Imipramine (50 μmol/L) showed no effect on APD90,although significantly decreased Vmax to about 69%, APD50 to about 84%. 3. In isolated guinea pig ventricular myocytes study,imipramine inhibited TTX sensitive Na current in a dose-dependent manner, to about 77% in the present of 50 μmol/L and toabout 56% in the present of 100 ìmol/L, respectively. 4. Imipramine (1.5 mg/kg, i.v.) hardly prolonged any QTc in consciousdogs, nor in anesthetized condition. Conclusion: The simultaneously depression of IKr and Na current should be responsible forthe no-change of APD90 and QTc. The difference in the extent of the inhibition in different channels would lead the differenteffect on APD, hence QT interval.

doi:10.1016/j.vascn.2007.02.012

THE USE OF PULMONARY PRESSURE–VOLUME MEASUREMENTS TO DETECT INDICES OF LUNG INJURY

Martin Sanders, Chin-hu Huang, Stephen Foote

Pfizer Inc., Groton, CT, USA

Pulmonary pressure–volume curves (PV-loop) have been used to characterize the mechanical behavior of the total respiratorysystem in both research and clinical settings. We explored the use of PV-loop measurements to determine the level of acute lunginjury induced by alpha-naphthylthiourea (ANTU), an agent that damages the pulmonary endothelium, with and without theaddition of high volume ventilation (HVV), a maneuver used to create mechanical lung damage. Compared to the normalventilation volume of 3 mL/kg at a rate of 90 breaths per minute (BPM), HVV utilizes a ventilation volume of 13.4 mL/kg at arate of 35 BPM. Using the FlexiVent, (Scireq), we compared changes in quasi-static compliance (Cst) and curvature parameter(K) of the PV-loop in the Sprague–Dawley rat. The animals were anesthetized with ketamine/xylazine, tracheotomized andconnected to the FlexiVent, ventilator. Rats dosed 4 h earlier with ANTU at 50 mg/kg i.p. did not show a significant differencein their pulmonary mechanical properties compared with rats treated with DMSO vehicle. Animals receiving HVV alone hadlung injury, revealed as changes in Cst and K compared with rats under normal volume ventilation. In addition, the indices oflung injury were potentiated in rats treated with ANTU plus HVV. In conclusion, we have demonstrated that the combination ofANTU and HVV resulted in significant changes in lung mechanical properties and that PV-loop analysis is a useful measure forassessing the damage to the lung.

doi:10.1016/j.vascn.2007.02.013