e3Meeting abstracts

COMPARISON OF PULMONARY MECHANICS IN NAÏVE SPRAGUE–DAWLEY AND BROWN NORWAY RATS

Martin Sanders, Chin-hu Huang, Colette Thorp

Pfizer, Inc., Groton, CT, USA

We compared and characterized the airway properties of naïve male Brown Norway (BN) and Sprague–Dawley (SD) rats todetermine if we could detect innate differences in their airway sensitivity. In addition, we carried out pressure–volume (PV-loop)measurements to see if these two strains differed in their pulmonary mechanical properties. Using the FlexiVent® (Scireq), wecompared changes in pulmonary resistance, compliance and elastance to sequentially administered APNEA (1 mg/kg), an adenosine3 agonist that promotes degranulation of rat mast cells and to methacholine (80 μg/kg), a muscarinic bronchoconstrictor agent.Baseline values in resistance (R: cmH2O

.s/mL), compliance (C: mL/cmH2O) and elastance (E: cmH2O/mL) were not differentbetween the two strains, SD vs. BN (R: 0.118±0.03 vs. 0.108±0.05), (C: 0.275±0.08 vs. 0.267±0.06), (E: 3.65±0.25 vs. 4.01±1.2).Responses to APNEA (R: 0.361±0.13 vs. 0.254±0.13), (C: 0.208±0.03 vs. 0.235±0.05), (E: 4.87±0.66 vs. 4.65±1.3) or tomethacholine(R: 1.08±0.32 vs. 1.31±0.55), (C: 0.110±0.03 vs. 0.082±0.03), (E: 9.40±1.7 vs. 13.4±3.8) were similar between the strains. For PV-loopmeasurements, the baseline quasi-static compliance (Cst) and loop curvature parameter (K) were similar between the two strains, SD vs. BN(Cst: 0.764±0.05 vs. 0.817±0.16) and (K: 0.156±0.02 vs. 0.166±0.01). These data suggest that there is no inherent advantage in choosingone unsensitized rat strain over the other for the purpose if assessing the lung mechanical properties or responses to test agents onrodent pulmonary function.

doi:10.1016/j.vascn.2007.02.006

SAFETY PHARMACOLOGY: AUTOMATED NEUROMUSCULAR FUNCTION TEST BATTERY

Genevieve Gagnon, Deborah Robinson, Pedro Tan, Terri Banchero, Jaime Monsere, Lonnie Grantham, Tiffini Brabham

Pfizer Global Research & Development, Ann Arbor, MI, USA

Historically neurobehavioral testing has been a labor-intensive, manual process. In order to increase efficiency and reduce inter-experimenter variation an automated quantitative neuromuscular test system was validated. Impaired neuromuscular function in rats,induced by chlorpromazine (CLZ), was assessed using the following automated instruments: hind-limb footsplay, grip strength, rota-rod, treadmill, forced swim and forced wheel running devices. Six to Eight Sprague–Dawley male (M) and female (F) ratswere administered a single dose of vehicle or CLZ at 10 mg/kg by gavage. Testing procedures were performed between 1 and 5 hourspost dose.

Table of Resultsa b

Device

Measurement CLZ treatment outcome

Hind-limb footsplayc

Loss of hind-limb muscle tone z25% Landing footsplay distance Rota-rodc Rotating rod walking latency A41% Rod walking time Treadmillc Moderate walking (1-day, 10–20 m/min,

6° incline for 10–20 min)

A26% Walking distance

Forced swim

Swim endurance z75% M (Immobility) z180% F

Forced wheel running

Run endurance A57% M (Distanced traveled) A91% F

aResults depict significant CLZ mean value differences as compared to vehicle control (pb0.05).bThere was no significant difference detected in dose-groups using the forelimb grip strength device.cTests were performed in males only.

These data support the sensitivity of these procedures for defining drug related effects on neuromuscular function, and suggest thata semi-automated tier II test battery can be used as part of the safety pharmacology neurofunctional-screening package.

doi:10.1016/j.vascn.2007.02.007