vessels is possible, and toxic effects on morphology can be quicklymeasured with the combined data acquisition and analysis software.

doi:10.1016/j.vascn.2011.03.185

Poster No: 181

Time course of hypoxic-induced changes in pulmonary arterialpressures in anesthetized dogs exposed to FiO2s of 12% and 10%:A model of vascular pulmonary hypertensionPedro A. Vargas-Pinto a, Adriana M. Pedraza-Toscano a,Carlos del Rio b, Robert L. Hamlin a, b

a The Ohio State University, Columbus Ohio, United Statesb Qtest Labs, Columbus Ohio, United States

This study was conducted to characterize the hypoxic caninemodel of pulmonary hypertension.

Methods: Nine dogs were anesthetized and instrumented torecord pressures from the right ventricle (RV), PAP and systemicarterial blood gases. Effort of ventilation was approximated as thedifference in RV end-diastolic pressure (EDP) between the respiratorypause and peak inspiration. Energetics of ventilation was approxi-mated as the “double-product” of respiratory rate (RR) and effort.Dogs were exposed to FiO2 values of 0.21, 0.12, and 0.10.

Results: Within 2 min of substituting either 0.12 or 0.10, steadystates of most parameters occurred. PaCO2 remained unchanged.PaO2 decreased from 66 to 39 mm Hg at 0.12, and to 29 mm Hg at0.10. RR increased from ~13/min to ~28/min. Difference between RVEDP during the respiratory pause and during peak inspirationincreased from ~6 mm Hg to ~16 mm Hg for 0.12 and to ~14 mmHg for 0.10. The “double-product” during the final minutes eitherplateaued for 0.12 or decreased for 0.10. PAP increased from ~11.5 mmHg to ~12.5 mm Hg for 0.12 and to ~14 mm Hg for 0.10.

Discussion/importance: This study confirmed the well-knowneffects of hypoxia on PaO2, RR and effort. However in this study atendency for stiffening of the pulmonary trunk was seen for both 0.12and 0.10, but greater for 0.10. Moreover the “double-product”increased for both levels of hypoxia, but tended to either plateau oractually decrease after 5 min of hypoxia, implying fatigue of musclesof respiration.

doi:10.1016/j.vascn.2011.03.186

Poster No: 182

Animal models of pulmonary hypertensionKristy D. Bruse, Vijay Naik

Lovelace Respiratory Research Institute, Albuquerque, New Mexico, USA

Pulmonary arterial hypertension (PAH) is not a disease per se but apathophysiological parameter defined as a mean pulmonary arterialpressure≥25mmHg at rest. Although disease-specific pharmaceuticalcompounds currently in use have improved quality of life in patientswith PAH, as a group, they have not improved survival compared toplacebo. The most common models used for pre-clinical drug researchare themonocrotaline (MC) lung injurymodel and chronic hypoxic (CH)exposure model. This study describes two models, one a model of PAH(MC) and the other a model of pulmonary hypertension secondary tohypoxia (CH). Male Sprague–Dawley (Lung Injury) or Wistar (CHModel) rats were used. Animals were treated with a single injection ofMC or vehicle (injury) or placed in environmental exposure chambers

for up to 2 weeks (CH). Right ventricular systolic pressure (RVSP), rightheart weight (RHW), and vascular wall remolding were measured insubsets of animals on days 7, 14, 28 and 42. RVSP was significantlyelevated in MC treated animals. RHW in MC treated animals wassignificantly elevated at day 28. RVSP and RWH were significantlyelevated in CH. Both models exhibited vascular wall thickening. Inconclusion, although both models exhibit elevated right ventricularsystolic pressure, vascular wall thickening, and RWH, there is no good,verified, evidence that any currently available animal models demon-strate the severe angioproliferative lesions observed in human PAH.Animal models which better recapitulate human disease are needed forpre-clinical drug development.

doi:10.1016/j.vascn.2011.03.187

Poster No: 183

Assessment of respiratory function—Comparisons betweenheadout and whole body plethysmographyPhilippa J. Priestley

Covance Laboratories Ltd., Harrogate, UK

Assessment of respiratory function is a requirement of theregulatory authorities for pre-clinical studies. The standard set-upin our laboratory involves the use of whole-body plethysmographs(supplied by EMMS) where the animals are freely moving. Theplethysmographs are connected via a differential pressure transdu-cer to the ‘eDacq’ (EMMS data acquisition) system for recording ofrespiratory parameters. In response to a number of requests fordose administration by inhalation we have more recently utilizedthe plethysmograph restraint tubes to enable respiratory parametermonitoring prior to, during and after inhalation exposure. Con-sideration had to be taken as to the effect(s) the restraint proceduremay have on the animals' respiratory parameters. In view of thisand to minimize the stress caused to the animals they wereacclimatized to the restraint tubes on a number of occasions forgradually increasing time intervals prior to the day of respiratorymonitoring.

This poster describes data from both freely moving and restrainedrespiratory monitoring systems, the comparable limitations of eachmethod and the effects on respiratory parameters, that as expected,reflect a higher ‘stress’ level in the restrained rats…reflected in forexample a generally higher respiratory rate and subsequently lower tidalvolume that are reflected as the expected changes in other parametersand the implications of this, in study design and data analysis.

doi:10.1016/j.vascn.2011.03.188

Poster No: 184

A method for the assessment of respiratory function injuvenile ratsKevin Norton, Helen Penton, Stephanie Carrier, Mark Vezina

Charles River Laboratories, Montreal, Canada

It has been reported that 90% of all medicines used in infants andchildren have undergone preclinical safety evaluation in adultanimals only. This has led to additional regulation from both theEMEA and the FDA requiring that bridging studies be conducted injuvenile animals. The EMEA regulations state “Situations which

Abstractse54

would justify toxicity studies in juvenile animals include, but are notlimited to, findings in non-clinical studies that indicate target organor systemic toxicity relevant for developing systems, possible effectson growth and/or development in the intended age group or if apharmacological effect of the test compound will affect developingorgan(s)”. The objective of this study was to evaluate the feasibilityof assessing respiratory function in juvenile rats. Respiratoryfunction was assessed in conscious non-restrained juvenile ratsusing a whole-body plethsymograph. Animals were acclimated for15 min prior to conducting a 30-min assessment post-treatment.Animals received a single dose of baclofen, a known respiratorydepressant, at 2.5 or 5 mg/kg, on Days 7, 18, 26 and 38 postpartumwhich resulted in a reduction in respiratory rate and overall minutevolume indicating that this juvenile rat model could detect changesin respiratory function. These data confirm that Safety Pharmacol-ogy assessments can be adapted to meet the growing requirementfor additional safety assessments in juvenile toxicity studies and,that existing models can be tailored to provide sensitive assess-ments of both toxicological and pharmacological effects on respira-tory function in juvenile rats.

doi:10.1016/j.vascn.2011.03.189

Poster No: 185

Pulmonary arterial hypertension induced by low oxygenenvironment in the presence of VEGF receptor antagonismPeter B. Senese, Douglas L. Janssen, Melissa D. Fisher,Jinbao B. Huang, Michael R. Gralinski

CorDynamics, Chicago, IL, USA

The objective of this study was to continue validating a clinically-relevant model of pulmonary artery hypertension in the rat. Previouswork in the rat has demonstrated the development of increasedpulmonary artery pressures, hypertrophy of the pulmonary arterialvascular smooth muscle, and proliferation of the endothelial vascularlumen following extended exposure to hypoxia and VEGF-receptorantagonist. Initially, we determined that rapid exposure to severehypoxia (10% oxygen, 22,000 ft above sea level equivalency) wasassociated with dyspnea, lethargy, and other adverse clinicalobservations in the Sprague–Dawley rat. In order to maximizelonger-term survival and optimize interrogation of test article efficacyagainst pulmonary artery hypertension, we refined the model asoutlined below. Male Sprague–Dawley rats (200–250 g) were kept intheir home cages inside a hypoxic tent. Baseline atmospheric oxygen(21%, Chicago, IL — 600 ft above sea level) was reduced to 13.5%(11,000 ft above sea level equivalency) using an oxygen scrubbinggenerator. Prior to placement inside the tent, each rat received asingle dose of either semaxanib (200 mg/kg, i.p.) or vehicle control(DMSO). Rats were maintained inside the tent for three weeks. Afterthis period, rats were removed, anesthetized, and instrumented formeasurement of terminal right ventricular, pulmonary, and systemicarterial pressures along with thoracic organ weights. Rats receivingthe VEGF receptor antagonist followed by exposure to low oxygenconditions for three weeks had significantly elevated right ventricularpressures (RVSP), pulmonary artery pressures (systolic [SPAP], mean[MPAP], diastolic [DPAP]), and hypertrophic hearts (right ventricle[RV]/left ventricle [LV]+septum [S] ratio) in comparison to normoxicand hypoxic plus vehicle-exposed rats.

doi:10.1016/j.vascn.2011.03.190

Poster No: 186

Hyper- and hypothermia and the effect on respiration in the ratFrida Martinsson, Margareta Some, Ann-Christin Ericson

Dept Safety Pharmacology, Safety Assessment, AstraZeneca R&D,Södertälje, Sweden

The effect of hyper- and hypothermia on respiration was studiedin male Wistar rats (n=10/group). Respiratory rate and tidal volume(VT) were measured by whole body plethysmography and core bodytemperature by radio telemetry. The hyperthermia was induced by aVanilloid Receptor 1 (VR1)-antagonist (250 μmol/kg, po) andhypothermia by paracetamol (1650 μmol/kg, ip). The VR1-antagonistwas also administered in combination with paracetamol in order toabolish the hyperthermia. Vehicle was used as control. The algorithmfor computing tidal volume is body temperature-dependent andcorrection was done accordingly resulting in VTC-values. Hyperther-mia persisted for 3.5 h following dosing of the VR1-antagonist.Following VR1-antagonist+paracetamol, hyperthermia was abol-ished at 1 h following dosing after which a progressing hypothermiastarted. A transient increase in VTC, was observed immediately afterdosing of VR1-antagonist or VR1-antagonist+paracetamol. There-after the rats with hyperthermia showed VTC similar to vehicletreated rats while VTC increased during hypothermia in the ratsreceiving the combination. Paracetamol administered alone immedi-ately caused a progressing hypothermia with a decrease in VTC for~2 h following dosing. The changes observed in VTC, as well as inrespiratory rate and minute volume, do not seem to be correlatedwith the hyper- or hypothermia in the temperature range of 35–38 °Ccurrently studied.

doi:10.1016/j.vascn.2011.03.191

Poster No: 187

Sensitivity of implantable respiratory telemetry withnon-restrained cynomolgus monkeys in the Latin square designLoell B. Moon a, Robert Kaiser b, Roy Erwin b,Douglas Regalia b, Stephen Tichenor b

a Data Sciences International, New Brighton, MN, USAb Charles River Laboratories Preclinical Services Nevada,6995 Longley Lane, Reno NV, USA

Implantable respiratory telemetry could be a desirable alternativeto jacketed approaches in stand-alone SP and combined Tox/SP largemolecule studies and is now available in the D70-PCTR. The goal ofthis study was to assess the statistical sensitivity of this respiratoryassessment methodology within the Latin square (LS) paradigm.

Method: 5 cynomolgus monkeys were implanted with DSI D70-PCTR transmitters and dosed in a LS design (acepromazine SQ at 0,0.1, 0.5, and 1.5 mg/kg). Data included tidal volume (TV), respiratoryrate (RR), and minute volume (MV). ANCOVA and Power statisticsanalyses were conducted to evaluate significant difference (SD)results and to determine the minimal detectable change in respira-tory parameters (MDD) at 80% Power for Ns of 4 and 8 animals. Lightvs. dark period SD were also evaluated. Lastly, a 2nd MDD (MDD2)was determined using the 1st 9 h post-Rx and w/o adjustments forday and sequence (no SD).

Results: Tests of SD for TV, RR, and MV vs. controls indicated SDbetween light and dark periods (P=0.001), while no SD weredetected from dosing. MDD1 values were 36, 11, and 42% (N=4) and

Abstracts e55