Drug-induced effects on cardiovascular function in pentobarbital anesthetized guinea-pigs: Invasive LVP measurements versus the QA interval

Bio-Plus Safety Pharmacology, Vlasmeer 5/0003, B-2400 Mol, Belgium.
Journal of pharmacological and toxicological methods (Impact Factor: 2.39). 07/2012; 66(2):152-9. DOI: 10.1016/j.vascn.2012.07.002
Source: PubMed


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.

1 Follower
29 Reads
  • [Show abstract] [Hide abstract]
    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 3h (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, and 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.
    No preview · Article · May 2013 · Journal of pharmacological and toxicological methods
  • [Show abstract] [Hide abstract]
    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.
    No preview · Article · Nov 2013 · Journal of pharmacological and toxicological methods
  • [Show abstract] [Hide abstract]
    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.
    No preview · Article · Jan 2014 · Reproductive sciences (Thousand Oaks, Calif.)
Show more