Optimising conditions for studying the acute effects of drugs on indices of cardiac contractility and on haemodynamics in anaesthetized guinea pigs.
ABSTRACT Detecting adverse effects of drugs on cardiac contractility is becoming a priority in pre-clinical safety pharmacology. The aim of this work was to optimise conditions and explore the potential of using the anaesthetized guinea pig as an in vivo model.
Guinea pigs were anaesthetized with Hypnorm/Hypnovel, isoflurane, pentobarbital or fentanyl/pentobarbital. The electrocardiogram (ECG), heart rate, arterial blood pressure and indices of cardiac contractility were recorded. In further experiments in fentanyl/pentobarbital anaesthetized guinea pigs the influence of bilateral versus unilateral carotid artery occlusion on haemodynamic responses was investigated and the effects of inotropic drugs on left ventricular (LV) dP/dt(max) and the QA interval were determined.
Pentobarbital, given alone or after fentanyl, provided suitable anaesthesia for these experiments. Bilateral carotid artery occlusion did not alter heart rate or arterial blood pressure responses to isoprenaline or angiotensin II. Isoprenaline and ouabain increased LVdP/dt(max) and decreased the QA interval whereas verapamil had opposite effects and strong inverse correlations between LVdP/dt(max) and the QA interval were found.
Conditions can be optimised to allow the pentobarbital-anaesthetized guinea pig to be used for simultaneous measurement of the effects of drugs on the ECG, haemodynamics and indices of cardiac contractility. The use of this small animal model in early pre-clinical safety pharmacology should contribute to improvements in detecting unwanted actions on the heart during the drug development process.
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ABSTRACT: Utilization of implantable bio-telemetry devices represents a common approach to contemporary cardiovascular safety assessment. Depending on the specific needs of the study design, and corresponding surgical methodologies employed, application of telemetry devices may have more or less liability to interact with ongoing physiology. The potential for intrathoracic procedures (epicardial/intracardiac ECG lead arrangements, left ventricular catheterization) to influence baseline cardiovascular function, and particularly arrhythmia status is currently an important topic of consideration. Two experiments were performed to assess the post-surgical incidence of ventricular arrhythmias in cynomolgus monkeys instrumented with telemetry devices with 1) left ventricular pressure (LVP) transducers and epicardial lead array (N=67), and 2) epicardial lead array without LVP catheter placement (N=55). A third experiment (N=18) was performed to prospectively, and definitively, investigate the effect of chronic left ventricular catheterization on the observed incidences of arrhythmias by means of multiple (pre- and post-surgery) electrocardiographic evaluations conducted on ~24hours of data per interval assessed up to ~12months post-implantation. The diversity and number of ventricular rhythm variants was considerably greater in animals instrumented with left ventricular catheters (62/67; 93%) compared to animals instrumented with epicardial leads only, (21/55; 38.2%) and surgically naïve animals (9/18; 50%). Prior to surgery, the average frequency of all definitively characterized arrhythmias among experimentally naïve animals was 0.19/hour; following surgical implantation of the telemetry device with epicardial leads and ventricular pressure catheter, the overall frequency of arrhythmia increased approximately 40-fold, to 7.19/hour. Similar to prior investigations in canines, the present results confirm an increased incidence in the rate and variety of ventricular arrhythmias in cynomolgus monkeys when instrumented with telemetry devices equipped with LVP catheters. Instrumentation with epicardial leads was not associated with an increase in arrhythmias above that expected as a function of normal biological variation in experimentally naïve animals of this species.Journal of pharmacological and toxicological methods 11/2013; · 2.32 Impact Factor
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ABSTRACT: The sodium-potassium pump is widely recognized as the principal mechanism for active ion transport across the cellular membrane of cardiac tissue, being responsible for the creation and maintenance of the transarcolemmal sodium and potassium gradients, crucial for cardiac cell electrophysiology. Importantly, sodium-potassium pump activity is impaired in a number of major diseased conditions, including ischemia and heart failure. However, its subtle ways of action on cardiac electrophysiology, both directly through its electrogenic nature and indirectly via the regulation of cell homeostasis, make it hard to predict the electrophysiological consequences of reduced sodium-potassium pump activity in cardiac repolarization. In this review, we discuss how recent studies adopting the systems biology approach, through the integration of experimental and modeling methodologies, have identified the sodium-potassium pump as one of the most important ionic mechanisms in regulating key properties of cardiac repolarization and its rate dependence, from subcellular to whole organ levels. These include the role of the pump in the biphasic modulation of cellular repolarization and refractoriness, the rate control of intracellular sodium and calcium dynamics and therefore of the adaptation of repolarization to changes in heart rate, as well as its importance in regulating pro-arrhythmic substrates through modulation of dispersion of repolarization and restitution. Theoretical findings are consistent across a variety of cell types and species including human, and widely in agreement with experimental findings. The novel insights and hypotheses on the role of the pump in cardiac electrophysiology obtained through this integrative approach could eventually lead to novel therapeutic and diagnostic strategies.Pflügers Archiv - European Journal of Physiology 02/2014; 466(2):183-193. · 4.87 Impact Factor
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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), and 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.Toxicological Sciences 11/2013; · 4.48 Impact Factor