Drug effects on the CVS in conscious rats: separating cardiac output into heart rate and stroke volume using PKPD modelling

Abstract

Background and purpose: Previously, a systems pharmacology model was developed characterizing drug effects on the interrelationship between mean arterial pressure (MAP), cardiac output (CO) and total peripheral resistance (TPR). The present investigation aims to (i) extend the previously developed model by parsing CO into heart rate (HR) and stroke volume (SV) and (ii) evaluate if the mechanism of action (MoA) of new compounds can be elucidated using only HR and MAP measurements.

Experimental approach: Cardiovascular effects of eight drugs with diverse MoAs (amiloride, amlodipine, atropine, enalapril, fasudil, hydrochlorothiazide, prazosin and propranolol) were characterized in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats following single administrations of a range of doses. Rats were instrumented with ascending aortic flow probes and aortic catheters/radiotransmitters for continuous recording of MAP, HR and CO throughout the experiments. Data were analysed in conjunction with independent information on the time course of the drug concentration following a mechanism-based pharmacokinetic-pharmacodynamic modelling approach.

Key results: The extended model, which quantified changes in TPR, HR and SV with negative feedback through MAP, adequately described the cardiovascular effects of the drugs while accounting for circadian variations and handling effects.

Conclusions and implications: A systems pharmacology model characterizing the interrelationship between MAP, CO, HR, SV and TPR was obtained in hypertensive and normotensive rats. This extended model can quantify dynamic changes in the CVS and elucidate the MoA for novel compounds, with one site of action, using only HR and MAP measurements. Whether the model can be applied for compounds with a more complex MoA remains to be established.

Figure 1

Comparison between the basic CVS model to characterize drug effects on the interrelationship between MAP, CO and TPR and the extended CVS model to characterize drug effects on the interrelationship between MAP, CO, HR, SV and TPR. Extended CVS model: CO equals the product of HR and SV (CO = HR × SV) and MAP equals the product of CO and TPR (MAP = CO × TPR). SV is influenced by indirect feedback through MAP (SV_T) and by HR through a direct inverse log-linear relationship, where HR_SV represents the magnitude of this direct effect. Effects on HR, SV and TPR are described by three linked turnover equations. In these equations, K_{in_HR}, K_{in_SV} and K_{in_TPR} represent the zero-order production rate constants and k_{out_HR}, k_{out_SV} and k_{out_TPR} represent the first-order dissipation rate constants. When MAP increases as a result of a stimulating effect on HR, SV or TPR, the values of HR, SV and TPR will decrease as a result of the action of the different feedback mechanisms regulating the CVS. In this model, the magnitude of feedback on HR, SV and TPR is represented by FB. System-specific parameters are indicated in blue and drug-specific parameters are indicated in red.

Figure 2

Description of the handling effect and circadian rhythm in MAP, HR, CO, SV and TPR in SHR (A) and WKY rats (B) after vehicle administration. Data are from study 1 and study 2 from all treatment groups. Handling of the rats caused a temporary increase in HR, TPR, CO and MAP and decrease in SV that was independent of drug exposure. The handling effect is visible at 1000 h that is when the rats were dosed with vehicle as indicated by the arrows. Two SHR were also dosed at 1300 h (not indicated in the plot). The grey dots represent the observations, which are connected by the continuous grey lines, the dashed black lines represent the mean of the observations and the continuous black lines represent the population prediction by the developed extended CVS model.

Figure 3

Description of the effects of amlodipine in SHR (A) and WKY rats (B). 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. Amlodipine has an inhibitory effect on TPR. Therefore, TPR decreases after administration of amlodipine. As a result of the indirect feedback, HR, SV and CO increase. In addition, the initial decrease in SV is related to the direct inverse relationship between HR and SV. MAP changes in the same direction as the initial effect that is MAP decreases. The grey and black dots represent the observations from two different rats. The continuous and dashed lines represent the effects of amlodipine on individuals and the population predicted by the developed extended CVS model.

Figure 4

Properties of the CVS. The system properties of the CVS were investigated by simulating the response on MAP, CO, HR and TPR after inhibiting HR (A), SV (B) or TPR (C). Inhibiting HR, SV or TPR always resulted in a decrease in MAP, which demonstrates that feedback cannot be stronger than the primary effect. In addition, the delayed response of the MAP was longer when the drug effect was on SV as compared with TPR.

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.