Cellular impedance assays for predictive preclinical drug screening of kinase inhibitor cardiovascular toxicity.

Cardiovascular (CV) toxicity is a leading contributor to drug attrition. Implementing earlier testing has successfully reduced human Ether-à-go-go-Related Gene-related arrhythmias. How- ever, analogous assays targeting functional CV effects remain elusive.

5HT1A receptors inhibit glutamate inputs to cardiac vagal neurons post-hypoxia/hypercapnia.

Synaptic inputs to cardiac vagal neurons (CVNs) regulate parasympathetic activity to the heart. Previous work has shown insults such as hypoxia and hypercapnia (H/H) alter CVN activity by activating post-synaptic serotonergic, purinergic, and glutamatergic receptors in CVNs. This study examines the role of serotonergic 5HT1A receptors in modulating these excitatory neurotransmissions to CVNs during control conditions, H/H and recovery from H/H.

An integrative pharmacological approach to radio telemetry and blood sampling in pharmaceutical drug discovery and safety assessment.

Background: A successful integration of the automated blood sampling (ABS) and telemetry (ABST) system is described. The new ABST system facilitates concomitant collection of physiological variables with blood and urine samples for determination of drug concentrations and other biochemical measures in the same rat without handling artifact.

Method: Integration was achieved by designing a 13 inch circular receiving antenna that operates as a plug-in replacement for the existing pair of DSI's orthogonal antennas which is compatible with the rotating cage and open floor design of the BASi Culex® ABS system.

Combining radio telemetry and automated blood sampling: a novel approach for integrative pharmacology and toxicology studies.

Introduction: A novel automated blood sampling and telemetry (ABST) system was developed to integrate pharmacokinetic (PK), pharmacodynamic (PD) and toxicology studies. The goals of this investigation were to determine: 1) optimal feeding conditions and minimal acclimation times for recording PD parameters (blood pressure, heart rate, and temperature) after animals arrived on-site; 2) stress hormone levels in ABST-housed rats; 3) the feasibility of simultaneously recording cardiovascular parameters with electroencephalogram (EEG); 4) the equivalence of renal endpoints from ABST-housed rats with those in the metabolic cage, and 5) the cardiovascular responses to baclofen.

Methods: Body weight, blood pressure, temperature, stress biomarkers, urine chemistries, renal biomarkers and responses to vehicle or baclofen (10mg/kg) were compared in awake and freely moving rats housed in the ABST system, home cage (HC) or metabolic cage.

Reactive oxygen species mediate central cardiorespiratory network responses to acute intermittent hypoxia.

Although oxidative stress and reactive oxygen species generation is typically associated with localized neuronal injury, reactive oxygen species have also recently been shown to act as a physiological signal in neuronal plasticity. Here we define an essential role for reactive oxygen species as a critical stimulus for cardiorespiratory reflex responses to acute episodic hypoxia in the brain stem. To examine central cardiorespiratory responses to episodic hypoxia, we used an in vitro medullary slice that allows simultaneous examination of rhythmic respiratory-related activity and synaptic neurotransmission to cardioinhibitory vagal neurons.