Canine papillary muscle, action

Figure 5. Action potentials and developed tension recorded from canine papillary muscle before (A) and after 1 X 10 6 M (B) and 1 X 10 5 M (C) 2-n-butyl-MDl. Developed tension decreased by 25% (B) and 80% (C).

Preliminary electrophysiological studies with the tertiary MDIs demonstrated the ability of pr-MDI and bu-MDI to uncouple excitation-contraction coupling in superfused canine papillary muscle preparations at drug concentrations which do not reduce action potential characteristics including action potential amplitude, resting potential, duration at 25, 50, and 90% repolarization, and the rate of rise of phase 0 (59). This is taken as further evidence for an intracellular site of action of the MDIs. However, the electrophysiological effects of these agents appear to be quite complex (8,59). 

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. 

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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