A comprehensive model that describes the interaction between the cardiovascular system (CVS) and the intrathoracic pressure (ITP) based on a lumped parameter vascular representation and a time-varying elastance concept for the four cardiac chambers is presented. Special attention is given to two possible mechanisms of interventricular interaction; the constraining effects of the pericardium and direct interventricular interaction that results from the fact that the two ventricles share a common interventricular septum. The response of the CVS to positive and negative perturbations in the ITP and to injection of fluid into the pericardium was simulated and compared with experimental literature data. The results show that 1) the total heart volume is relatively constant throughout the cycle both for ITP of 0 and +15 mmHg, which is consistent with experimental data in dogs, thus suggesting that intrinsic properties of the cardiac chambers rather than a restricting pericardium is the mechanism for that observation. 2) The pericardium has a major role in modifying the transient and steady-state response to a step decrease in the ITP with a transient decrease in left ventricle (LV) end-diastolic volume followed by gradual increase afterwards. 3) The response to sudden injection of fluid into the pericardial space is a larger transient decrease in right ventricle than LV volume, which is consistent with experimental data. 4) Transmission across the septum has a relatively minor role in modifying the response of the CVS to negative pressure. Thus the model reasonably predicts the effects of intrathoracic and pericardial pressures on the circulation in a reflex-blocked animal and provides a means for placing multiple potential mechanisms in proper hierarchial order with regard to contributions to LV and overall CVS function.