Na+-Channel Modulation, a New Principle of Inotropic Intervention: Effects on Hemodynamic and Myocardial Energetics in the Immature Rabbit Heart

As chemists can easily produce large numbers of new potential drug candidates, there is growing demand for high capacity models that can help in driving the chemistry towards efficacious and safe candidates before progressing towards more complex models. Traditionally, the cardiovascular (CV) safety domain plays an important role in this process, as many preclinical CV biomarkers seem to have high prognostic value for the clinical outcome. Throughout the industry, traditional ion channel binding data are generated to drive the early selection process. Although this assay can generate data at high capacity, it has the disadvantage of producing high numbers of false negatives. Therefore, our company applies the isolated guinea pig right atrium (GPRA) assay early-on in discovery. This functional multi-channel/multi-receptor model seems much more predictive in identifying potential CV liabilities. Unfortunately however, its capacity is limited, and there is no room for full automation. We assessed the correlation between ion channel binding and the GPRA's Rate of Contraction (RC), Contractile Force (CF), and effective refractory frequency (ERF) measures assay using over six thousand different data points. Furthermore, the existing experimental knowledge base was used to develop a set of in silico classification models attempting to mimic the GPRA inhibitory activity. The Naïve Bayesian classifier was used to built several models, using the ion channel binding data or in silico computed properties and structural fingerprints as descriptors. The models were validated on an independent and diverse test set of 200 reference compounds. Performances were assessed on the bases of their overall accuracy, sensitivity and specificity in detecting both active and inactive molecules. Our data show that all in silico models are highly predictive of actual GPRA data, at a level equivalent or superior to the ion channel binding assays. Furthermore, the models were interpreted in terms of the descriptors used to highlight the undesirable areas in the explored chemical space, specifically regions of low polarity, high lipophilicity and high molecular weight. In conclusion, we developed a predictive in silico model of a complex physiological assay based on a large and high quality set of experimental data. This model allows high throughput in silico safety screening based on chemical structure within a given chemical space.

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“…Physiologically, a definite correlation between CF effects and the binding to Na ? [38][39][40] and Ca 2? [41] channels is expected.…”

Section: Resultsmentioning

confidence: 99%

Cardio-vascular safety beyond hERG: in silico modelling of a guinea pig right atrium assay

Fenu¹,

Teisman²,

Buck

et al. 2009

J Comput Aided Mol Des

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“…Hearts from neonatal (2 days) and adult (28 days) animals of either sex were used. Preparation of the hearts was done as described previously [17,18] . In brief: under general anesthesia and after abdominal incision and transection of the diaphragm, the hearts were cooled in situ with Ringer´s lactate solution at 4 ° C. Subsequently the hearts were rapidly excised and perfused in a retrograde fashion via the aorta according to Langendorff with a modifi ed Krebs-Henseleit solution.…”

Section: Animals and Surgerymentioning

confidence: 99%

Gene Expression of the Na<sup>+</sup>–Ca<sup>2+</sup> Exchanger, SERCA2a and Calsequestrin after Myocardial Ischemia in the Neonatal Rabbit Heart

et al. 2006

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Background: Neonatal hearts are less susceptible to developing myocardial dysfunction after hypoxia and/or ischemia than adult hearts. Differences in intracellular calcium homeostasis may be responsible for reduced calcium overload of the immature myocardium leading to the observed protection against ischemia. Objective: To assess differences in baseline and post-ischemic gene expression of calcium handling proteins after ischemia in neonatal and adult rabbit hearts. Methods: We used isolated antegrade perfused rabbit hearts (age 2 days, 28 days, n = 32), which were exposed to ischemia and hypothermia simulating myocardial stunning comparable to neonatal asphyxia. Gene and protein expression of the sodium–calcium exchanger (NCX), the sarco-endoplasmatic reticulum Ca²⁺-ATPase 2a (SERCA) and calsequestrin (CSQ) were measured using quantitative real-time PCR and Western blotting. Results: After ischemia and reperfusion in neonatal and adult hearts, a significant decrease in myocardial performance was recorded. At the mRNA level, significant differences in the baseline expression of NCX, SERCA and CSQ between neonatal and adult hearts were observed. In neonatal post-ischemic hearts, NCX and CSQ expression were significantly higher at the mRNA level than in controls. In contrast, SERCA expression remained unchanged in neonatal hearts and decreased in adult hearts compared to the non-ischemic controls. Conclusion: These findings suggest that changes in gene expression of calcium handling proteins may be involved in the different susceptibility of neonatal compared to adult hearts to developing myocardial dysfunction after ischemia.

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Current–Voltage Relationship for Late Na+ Current in Adult Rat Ventricular Myocytes

Clark

Giles

2016

Current Topics in Membranes

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Na+-Channel Modulation, a New Principle of Inotropic Intervention: Effects on Hemodynamic and Myocardial Energetics in the Immature Rabbit Heart

Cited by 4 publications

References 35 publications

Cardio-vascular safety beyond hERG: in silico modelling of a guinea pig right atrium assay

Cardio-vascular safety beyond hERG: in silico modelling of a guinea pig right atrium assay

Gene Expression of the Na<sup>+</sup>–Ca<sup>2+</sup> Exchanger, SERCA2a and Calsequestrin after Myocardial Ischemia in the Neonatal Rabbit Heart

Current–Voltage Relationship for Late Na+ Current in Adult Rat Ventricular Myocytes

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