Papillary muscle action potential assay

The Guinea Pig Isolated Papillary Muscle Action Potential Assay. 208... 

In this chapter, we will focus on the papillary muscle action potential assay and compare the predictive value of this model in terms of sensitivity and specificity to that of the IKr assay, the canine Purkinje fibre action potential and the in vivo dog and monkey QT. 

Specificity and Sensitivity of the Guinea Pig Papillary Muscle Action Potential Assay The QT PRODACT Initiative... 

Table 1 Sensitivity and specificity of the guinea pig papillary muscle action potential assay for QT and TdP liability using APD90 or APD3o 9o as predictive biomarkers. Predictive values were calculated for three tested pacing frequencies independently from the tested concentrations for all compounds. An in vitro result is considered positive for a compound if at least one concentration showed a statistically significant and/or > 10 % increase in the selected parameter (APD90 or APD3o 9o) vs. baseline values...

Table 6 Sensitivity and specificity of guinea pig papillary muscle action potential assay to predict the outcome of a clinical QT study. A preclinical result is considered positive for a compound if, at a preclinical concentration exposure (1-, 10- or 30-fold the unbound drug concentrations achieved in the clinic), a minunum 10 % increase in the selected parameter (APDgo or APD30-90) is observed...

The poor sensitivity of the guinea pig papillary muscle action potential assay should not lead the scientific community to disregard this preclinical model since its specificity should make it interesting. Indeed, it is accepted that there is no existing... 

Hayashi, S., Kii, Y, Tabo, M., Fukuda, H., Itoh, T., Shimosato, T., Amano, H., Saito, M., Morimoto, H., Yamada, K., Kanda, A., Ishitsuka, T., Yamazaki, T., Kiuchi, Y, Taniguchi, S., Mori, T., Shimizu, S., Tsurubuchi, Y, Yasuda, S., Kitani, S., Shimada, C., Kobayashi, K., Komeno, M., Kasai, C., Hombo, T. and Yamamoto, K. (2005) QT PRODACT A multi-site study of in vitro action potential assays on 21 compounds in isolated guinea-pig papillary muscles. Journal of Pharmacological Sciences, 99, 423-437. 

A next-level assay is usually an isolated heart/cardiac tissue preparation. The canine Purkinje fiber assay (GLP) measures several action potential parameters, like resting membrane potential, upstroke velocity, action potential duration and shape, but also if a drug acts reverse-use dependently [72]. Based on changes of the action potential shape it is possible to conclude which ion channels are modulated (e.g., L-type calcium channel block would abolish the plateau phase). The papillary muscle assay (e.g., guinea pigs) determines similar parameters [73]. 

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