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Abstract

The evaluation of proarrhythmic and hemodynamic liabilities for new compounds remains a major concern of preclinical safety assessment paradigms. Contrastingly, albeit functional liabilities can also translate to clinical morbidity and mortality, lesser preclinical efforts are focused on the evaluation of drug-induced changes in inotrope and lusitrope, particularly in the setting of concomitant hemodynamic/arrhythmic liabilities. This study aimed to establish the feasibility of an anesthetized guinea pig preparation to assess functional liabilities in the setting of simultaneous drug-induced electrocardiographic/hemodynamic changes, by evaluating the effects of various compounds with known cardiovascular properties on direct and indirect indices of left ventricular function. In short, twenty nine male guinea pigs were instrumented to measure electrocardiograms, systemic arterial pressure, and left ventricular pressure-volume relationships. After baseline measurement, all animals were given intravenous infusions of vehicle and two escalating concentrations of either chromanol 293B (n = 8), milrinone (n = 6), metoprolol (n = 7), or nicorandil (n = 8) for 10 minutes each. In all cases, these compounds produced the expected changes. The slope of preload-recruitable stroke work (PRSW), a pressure-volume derived load independent index, was the most sensitive marker of drug-induced changes in inotropy. Among the indirect functional indices studied, only the “contractility index” (dP/dtmax normalized by the pressure at its occurrence) and the static myocardial compliance (ratio of end diastolic volume and pressure) appeared to be adequate predictors of drug-induced changes in inotropy/lusitropy. Overall, the data confirms that both electrophysiological and mechanical liabilities can be accurately assessed in an anesthetized guinea pig preparation.

guinea pigs, inotrope, lusitrope, proarrhythmias, safety pharmacology.
© The Author 2013. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: [email protected].
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