Table 3.

Model assumptions

Number	Assumption	Clarification
1	All compounds influence the production rates of HR, SV or TPR rather than the dissipation rates.	This assumption is based on the MoA of the selected compounds (Table 4).
2	For compounds for which the maximum effect was not observed, complete inhibition (i.e. Emax = 1) was assumed at infinite concentrations to ensure identification of the EC50 parameter.	The validity of this assumption was evaluated for amlodipine using the basic CVS model (Snelder et al., 2013a). The influence of different values of the Emax (i.e. Emax = 0.8) on the estimates of the system parameters was tested.
3	The PK does not differ between rat strains and can be scaled between rabbit and rat on the basis of an allometric function (West et al., 1999; Anderson and Holford, 2009).	Although published information on the PK of all selected compounds was available, the PK was often evaluated in different rat strains and, for prazosin, even in a different species (rabbit).