hERG inhibition) and hemodynamics (various mechanisms). Here wedescribe techniques in the same model to measure changes in cardiacconduction (INa inhibition) and cardiac contractility (ICa inhibition).Lamotrigine, a mixed ion channel blocker used in the treatment ofbipolar depression, was used as a probe compound because of itscomplex electrophysiological profile. In vivo assessment of INa blockadewas made using several measurements: epicardial conduction timefrom stimulus spike to upstroke of left ventricularMAP signal (CT), Vmax

of MAP, QRS interval, and effective refractory period (ERP). Assessmentof ICa blockade was made via measurements of mean blood pressure(MBP) and maximum change of left ventricular pressure (contractility,LVdP/dt). Changes in theseparameterswere compared to IC50 values forNav1.5 (89 µM) and L-type calcium (41% inhibition at 300 µM) currentsdetermined by patch clamp electrophysiology. Lamotrigine causedexposure-dependent increases in CT, QRS, and ERP between 44 µM and211 µM free drug; Vmax was also decreased. Increases in CT duringventricular pacing appeared to be use and frequency dependent.Physiologically relevant decreases in MBP and LV dP/dt occurred at211 µM. These data demonstrate that sodium and calcium channelinhibition can be examined in the anesthetized guinea pig using analysisof cardiac conduction (↑CT, ↑QRS, ↑ERP, ↓Vmax) and inotropy (↓LV dP/dt).

doi:10.1016/j.vascn.2009.04.189

The relationship between hypoglycemia and changesin hemodynamics in conscious telemetry rats

Julia P. Li⁎, Li Xin, Cindy Cai, Songping Han, Paul C. LevesqueBristol-Myers Squibb, Hopewell, NJ, United States

Hypoglycemia induces counter-regulatory hormone responsesincluding epinephrine release, which could affect hemodynamics.The pre-clinical literature is inconsistent with respect to hemody-namic changes induced by insulin or hypoglycemic agents. Moreover,hemodynamic changes produced by drugs that cause hypoglycemiaare often attributed to hypoglycemia without consideration for off-target mechanisms. In the present study, hemodynamic responses tohypoglycemia induced by infusion of insulin or po dosing of an agentthat causes hypoglycemia (compound A) were evaluated in conscioustelemetry rats, and euglycemic glucose clamp technique was used todetermine whether maintaining euglycemia can ameliorate thehemodynamic responses. The right carotid artery and jugular veinof male Sprague-Dawley rats were cannulated with PE50 tubes forblood sampling and infusion of insulin or glucose. Rats wererandomized into 4 groups: 1) vehicle, 2) compound A at 300 mg/kg, 3) Compound A plus glucose clamp (120 mg/dL), 4) insulin,infused at rates to achieve similar blood glucose levels as withcompound A alone. Insulin and compound A produced similarhypoglycemia and qualitatively similar hemodynamic responses.The significant increase in pulse pressure induced by compound Awas completely prevented by the euglycemic glucose clamp proce-dure. The results are consistent with the hypothesis that the effect ofCompound A on pulse pressure is secondary to hypoglycemia, anddemonstrate the utility of this model.

doi:10.1016/j.vascn.2009.04.190

Continuous bloodpressuremeasurement in conscious, unrestrainedmonkeys using an implanted mouse transmitter

Andrea MitchellCovance Laboratories, Madison, WI, United States

Cynomolgus monkeys are commonly used in toxicological re-search. Accurate determination of blood pressure (BP) in conscious,unrestrained animals is currently only feasiblewith invasive telemetrytechniques. In this study, the functionality of a less invasive methodwas evaluated. A mouse BP transmitter (DSI, model PA-C10) wassurgically implanted subcutaneously and the catheter placed into afemoral artery of one male and one female monkey. BP and ECG datawere collected by jacketed external telemetry continuously for 24 h bi-weekly for 15 weeks. The BP and ECG signals were transmitted to aBluetooth receiver. Parameters evaluated were surgical implantationsite, quality of BP signals, data drop-out, systolic (SYS), diastolic (DIA),mean arterial (MAP) pressure, and pulse rate (PR). The incision siteshealed uneventfully. BP signals obtained were of excellent qualityduring light/dark cycles and did not interfere with ECG signals. Meanpressures (mmHg) and pulse rates (beats/min) during the light/darkcycles (30 min averages), respectively, were for the male: SYS: 90/90,DIA: 53/47, MAP: 71/66, PR: 107/125, and for the female SYS: 104/98,DIA: 64/61, MAP: 82/79, PR: 190/145, indicating that typicalphysiological values were obtained. Implantation of a PA-C10 BPtransmitter using a minimally invasive technique produced reliable BPdata for 24 h with insignificant data drop-out in conscious, unrest-rained non-human primates. This novel technique could be a viableoption for high quality ECG and BPmeasurements in toxicology studiesup to 15 weeks in length.

doi:10.1016/j.vascn.2009.04.191

Cardiovascular evaluation of sotalol in the telemeteredCynomolgus monkey

A. Wilson⁎, K. Semple, N. Lood, T. OshodiMaccine Pte Ltd, Singapore

The purpose of this study was to assess the potential effects ofSotalol on cardiovascular function in the telemetered Cynomolgusmonkey. Four Cynomolgus monkeys were surgically implanted withradio-telemetry transducers. Sotalol was given orally at doses of 0, 5,10, and 30 mg/kg. Mean arterial blood pressure, heart rate and Lead IIECG variables were monitored continuously recorded 1 h prior todosing and up to 6 h post dose. Data acquisition and analysis wereperformed using the DSI OpenART version 3.11/ NOTOCORD HEMversion 4.2. Sotalol produced a dose dependent reduction in heartrate and prolonged RR, PR, TT and corrected QT (QTc) intervals. Atransient increase in the QRS complex was also noted. Sotalol wasshown to produce a dose-dependent QTc prolongation over the doserange 5 to 30 m/kg, when given orally in the telemeteredCynomolgus monkey. The results from the study also add justificationto the use of the telemetered monkey in pre-clinical safety testing.

doi:10.1016/j.vascn.2009.04.192

Sulpiride-induced QTC prolongation and hERG channel blockade

Jin Zhai⁎, Dave Reynolds, Gregory Friedrichs, Ying-Ying ZhouSchering-Plough, Lafayette, NJ, United States

Sulpiride, a selective dopamine D2 receptor antagonist, has beenused primarily in the treatment of psychosis and depression. Thisdrug displayed dose-related QT prolongation or TdP in animals and inaged patients (Cmax≥1.2 µM). But mechanisms for the cardiactoxicity are unclear. This study evaluated effects of sulpiride on ECGparameters in telemetered monkeys and dogs. We also investigated

Abstracts / Journal of Pharmacological and Toxicological Methods 60 (2009) 210–258 257