cause motor dysfunction in humans, using a 1-metre enclosedwalkway, analysed by software developed in-house (Pawprint), incomparison with 3 other widely-used tests. Tests were conducted inorder of increasing impact on the animal: gait analysis → beamwalking→ rotarod→ LFS. Following pre-dose assessments, male HanWistar rats (n=8/group) were dosed with vehicle, ethanol (600–1200 mg/kg i.p.) or oxotremorine (0.03–0.1 mg/kg s.c.) and re-testedat 0.5 h post-dose. Pawprint measures several parameters; the mostuniversally affected was ‘speed of crossing’ (SOC). SOC was reducedby oxotremorine (from 0.06 mg/kg) whereas rotarod and beamwalking performance were decreased at 0.03 mg/kg. SOC wasunaffected by ethanol, at a dose that had effects in the rotarod, beamwalking and LFS (1200 mg/kg). In conclusion, gait analysis offers noclear advantage in sensitivity over existing methods, but could beviewed as a rapid, convenient test to incorporate into a test batteryalongside, say, rotarod and beamwalking, to assess effects of centrallyacting drugs on motor coordination in rodents.

References

Redfern, W. S., & Wakefield, I. D. (2006). Toxicology Testing Handbook(pp. 33−78). (2nd edn.). Informa Healthcare.

doi:10.1016/j.vascn.2010.11.007

Poster Number: 4Board Number: 4

The establishment of a hypoxic pulmonary vasoconstrictionmodel in the Cynomolgus MacaqueMelissa Fisher

Cordynamics, Inc., Chicago, IL, United States

The goal of this work was to establish a model of pulmonary arteryhypertension in the anesthetized monkeys. Although there areestablished models in the dog and rat, to our knowledge, this is thefirst validation of this method in the non-human primate. Ninemonkeys were used in the course of this study. A single dose ofketamine (5-10 mg/kg, IM) was given to move each monkey from itshome cage to the preparation area. Propofol (6-8 mg/kg, IV) was givento effect for intubation, bupivicaine (1 mg/kg, ID) was given at bothjugular and femoral incision sites. The monkeys were brought to asurgical suite andmechanically ventilated throughout the experiment.Four anesthetic methods explored included: a) isoflurane (1-2% MAC,inhaled), b) sodiumpentothal (15 mg/kg/hr, IV), c) fentanyl (10-25 μg/kg/hr, IV), and d) combination fentanyl (0.075 μg/kg/min, IV)/propofol(300 μg/kg/min, IV). Intravenous anesthesia was delivered via cali-brated infusion pump. Once the animals reached a surgical plane ofanesthesia, theywere instrumentedwith a Swan-ganz catheter via theright jugular vein to the pulmonary ‘wedge’ position to measure bothcardiac output and pulmonary arterial pressure. A Millar bloodpressure catheter was set in a carotid artery, and a femoral arterywas catheterized to take arterial blood gas samples. Other parametersmonitored included heart rate, respiratory rate, mucous membranecolor, capillary refill time and body temperature, as well as spO2 andETCO2 via pulse-oximetry. ECG and blood pressure were recorded viaNotocord data acquisition system. Throughout instrumentation,animals were ventilated with 100% O2. Once instrumentation wascomplete, the ventilation was switched from 100% O2 to alternatingsessions of normoxia (20%O2/80%N2) andhypoxia (10%O2/90%N2) for30 minutes at each session over 3 hours. Isoflurane effectivelyprotected the monkeys against hypoxic pulmonary vasoconstrictionat paO2 levels as low as 27 mmHg (baseline: 145 mmHg). Sodium

pentothal did not provide an adequate anesthetic plane for the entireexperiment. As experiments progressed and hypoxic challenge wasrepeated, each monkey required increasingly larger volumes ofanesthesia which resulted in the death of some animals and unstablecardiopulmonary parameters in others. Fentanyl alone did not provideadequate anesthesia and required repeated bolus doses, resulting in anunstable preparation. The fentanyl/propofol combination maintainedan adequate anesthetic plane and did not require adjustment ofanesthetic doses. Once animals were started on each hypoxia phase, arobust increase in pulmonary arterial pressure (50-100% increase), amarked decrease in pO2 from blood gas samples, and a markeddecrease in spO2 via pulse-oximetery were noted. These valuesreturned to baseline during the alternating phases of normoxia. Toproduce consistent hypoxic pulmonary vasoconstriction in theCynomologous Macaque, the anesthetic combination of fentanyl(0.075 μg/kg/min, IV)/propofol (300 μg/kg/min, IV) was the mostsuccessful. This method provided an adequate surgical plane ofanesthesia for up to 5 hours and a significant increase of pulmonaryartery pressure during periods of hypoxia.

doi:10.1016/j.vascn.2010.11.008

Poster Number: 5Board Number: 5

Comparison of QT interval measurements in jacketed,radiotelemetry-implanted and anesthetized dogsKevin P. Fitzgerald, Alyssa Chaves, Richard Woltmann,Martha Hasbun-Manning, Gloria Zingaro, Katherine Bustard,Chao-Min Hoe, Joseph Salata, Pierre Morissette

Merck and Co., Inc., West Point, PA, United States

The present study was designed to compare four different dogmodels for measuring QT interval changes: jacketed telemetry andimplanted radiotelemetry in conscious dogs and vagus intact andvagus cut anesthetized dogs. Two well-known QT prolonging agentswere used to evaluate each model. Haloperidol Results: Increases inQTcf of 13 (5%), 26 (11%) and 31 (13%) msec in radio implanttelemetry were observed at 0.3, 1 and 3 mg/kg respectively. Increasesin QTcf of 32 (13%) and 52 (20%) msec in jacketed dogs wereobserved at 1 and 3 mg/kg but no test article-related effects wereobserved at 0.3 mg/kg. The vagus cut anesthetized dog modelincreased in a dose related fashion of 11 (3%), 27 (9%) and 43 (11%)msec at cumulative iv doses of 0.3, 1 and 3 mg/kg. The vagus intactanesthetized dog model increased in a dose related fashion of 36(8%), 58 (17%) and 82 (21%) msec at iv doses of 0.3, 1 and 3 mg/kg.EC5 were ~0.017, ~0.0036, 0.07 and 0.4 μM for the jacketed telemetry,radio implanted telemetry, vagus intact and vagus cut anesthetizeddog models respectively. Moxifloxacin Results: Increases in QTcf of 14(6%), 27 (12%) and 45 (20%) msec in radio implant telemetry wereobserved at 10, 30 and 100 mg/kg respectively. Increases in QTcf of 35(17%) and 53 (24%) msec in jacketed dogs were observed at 30 and100 mg/ kg but no test article-related effects were observed at 10 mg/kg. The vagus cut anesthetized dog model increased 7 (2%), 12 (3%)and 52 (12%) msec at cumulative iv doses of 3, 10 and 30 mg/kg. Thevagus intact anesthetized dog model increased QTc 26 (6%), 38 (9%)and 74 (20%) msec at cumulative iv doses of 3, 10 and 30 mg/kg. EC5were 16, 5.2, 40.8 and ~70.0 μM for the jacketed telemetry, radioimplanted telemetry and the vagus intact and vagus cut anesthetizeddog model respectively. All models investigated detected QTc intervalprolongation after administration of the test articles. Based on EC5values, the implanted telemetry model was most sensitive fordetecting QTc changes. While the jacketed model is slightly less

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