Drug-induced effects on cardiovascular function in pentobarbital anesthetized guinea-pigs: Invasive LVP measurements versus the QA interval
ABSTRACT Evaluation of drug-related effects on cardiovascular function is part of the core battery described in the ICH S7A guideline. Anesthetized guinea-pigs are excellent models for the evaluation of drug-induced prolongation of ventricular repolarization; however less information is available regarding other cardio-hemodynamic parameters in this model. The current study aimed to document cardio-hemodynamic responses in anesthetized guinea-pigs after administration of a number of reference drugs with known pharmacological actions.
Experiments were carried out in closed chest pentobarbital anesthetized female guinea-pigs. Compounds were administered intravenously while arterial blood pressure, left ventricular pressure (LVP) and the electrocardiogram were measured continuously. The rate of LVP contraction (LV dP/dt(max)) was used to evaluate cardiac performance; and was compared to the QA interval; which has previously been proposed as an indirect measurement of cardiac function.
Baseline values for heart rate and blood pressure were lower in anesthetized animals compared to literature data of conscious guinea-pigs. Heart rate increased after administration of adrenaline, isoprenaline and salbutamol, but not after L-phenylephrine. Verapamil and amiodarone decreased heart rate and blood pressure. Zatebradine infusion led to a decrease in heart rate with minimal effects on blood pressure. Sodium nitroprusside (SNP) caused a reduction in mean blood pressure at higher doses followed by reflex tachycardia. Both adrenaline and L-phenylephrine increased arterial blood pressure. Furthermore, adrenaline, isoprenaline and salbutamol increased LV dP/dt(max) and decreased the QA interval. L-phenylephrine increased LV dP/dt(max), but transiently prolonged the QA interval. Both verapamil and amiodarone decreased LV dP/dt(max) and prolonged the QA interval, whereas zatebradine did not affect this parameter.
In addition to its utility for the assessment of test compounds on ventricular repolarization the pentobarbital anesthetized guinea-pig model shows promise for early stage cardio-hemodynamic screening. Furthermore, the QA interval shows potential for prediction of adverse effects on cardiac contractility.
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ABSTRACT: INTRODUCTION: Early prediction of drug-induced functional cardiotoxicity requires robust in-vitro systems suitable for medium/high throughput and easily accessible cardiomyocytes with defined reproducible properties. The xCELLigence Cardio system uses 96-well plates with interdigitated electrodes that detect the impedance changes of rhythmic contractions of stem cell-derived cardiomyocyte (SC-CM) layers. Here, we report on our initial screening experience in comparison to established (multi)cellular and in-vivo models. METHODS: Impedance signals from human iPSC-CM (iCells™) and mouse eSC-CM (Cor.At™) were analyzed for contraction amplitude (CA) and duration, rise/fall time, beating rate (BR) and irregularity. RESULTS: Following solution exchange, impedance signals re-approximated steady-state conditions after about 2 (Cor.At™) and 3 hours (iCells™); these time points were used to analyze drug effects. The solvent DMSO (≤ 1%) hardly influenced contraction parameters in Cor.At™, whereas in iCells™ DMSO (> 0.1%) reduced CA and enhanced BR. The selective hERG K(+) channel blockers E-4031 and dofetilide reduced CA and accelerated BR (≥ 30 nM) according to the analysis software. The latter, however, was due to burst-like contractions (300 nM) that could be detected only by visual inspection of recordings, and were more pronounced in Cor.At™ as in iCells™. In cardiac myocytes and tissue preparations, however, E4031 and dofetilide have been reported to increase cell shortening and contractile force and to reduce BR. Compounds (pentamidine, HMR1556, ATX2, TTX, verapamil) with other mechanisms of action were also investigated; their effects differed partially between cell lines (e.g. TTX) and compared to established (multi)cellular models (e.g. HMR1556, ouabain). CONCLUSION: Mouse and human stem cell-derived cardiomyocytes respond differently to drugs and these responses occasionally also differ from those originating from established in-vitro and in-vivo models. Hence, drug-induced cardiotoxic effects may be detected with this system, however, the predictive or even translational value of results is considered limited and not yet firmly established.Journal of pharmacological and toxicological methods 05/2013; DOI:10.1016/j.vascn.2013.05.005 · 2.15 Impact Factor
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ABSTRACT: Prenatal hypoxia (HPX) reduces mitochondrial cytochrome c oxidase (CCO and COX) activity in fetal guinea pig (GP) hearts. The aim of this study was to quantify the lasting effects of chronic prenatal HPX on cardiac mitochondrial enzyme activity and protein expression in offspring hearts. Pregnant GPs were exposed to either normoxia (NMX) or HPX (10.5%O2) during the last 14 days of pregnancy. Both NMX and HPX fetuses, delivered vaginally, were housed under NMX conditions until 90 days of age. Total RNA and mitochondrial fractions were isolated from hearts of anesthetized NMX and HPX offspring and showed decreased levels of CCO but not medium-chain acyl dehydrogenase activity, protein levels of nuclear- and mitochondrial-encoded COX4 and COX1, respectively, and messenger RNA expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha, COX5b, and 4.1 compared to NMX controls. Prenatal HPX may alter mitochondrial function in the offspring by disrupting protein expression associated with the respiratory chain.Reproductive sciences (Thousand Oaks, Calif.) 01/2014; 21(7). DOI:10.1177/1933719113518981 · 2.18 Impact Factor
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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; DOI:10.1016/j.vascn.2013.11.001 · 2.15 Impact Factor