Figure 5.

Description of the effects of amlodipine on MAP and HR using the extended CVS model with the system-specific parameters fixed to values from Table 5, while assuming a stimulating effect on HR (A), an inhibitory effect on SV (B) or an inhibitory effect on TPR (C). Data are from study 1, in which vehicle and a different dose of amlodipine (0.3, 1, 3 and 10 mg kg⁻¹ p.o.) were administered on separate days. To evaluate if the site of action of amlodipine can be identified using only MAP and HR measurements, three hypotheses were evaluated. (i) Assuming amlodipine has a stimulating effect on HR resulted in an adequate description of the effect on HR. However, the description of the effect on MAP was inadequate as the directions of the observed and predicted effects were opposite. (ii) Assuming amlodipine has an inhibitory effect on SV resulted in an adequate description of the effect on HR and a reasonable description of the effect on MAP. However, the delay in the effect on MAP was overpredicted. (iii) Assuming amlodipine has an inhibitory effect on TPR resulted in an adequate description of the effect on HR and MAP. In conclusion, this model-based hypothesis testing indicated that it is most likely that the effect of amlodipine is on TPR, which is consistent with informationavailable from the literature. This indicated that the MoA of a compound can be elucidated using only MAP and HR measurements. The grey and black dots represent the observations of two different rats. The continuous and dashed lines represent the individual and population prediction.