To examine the factors contributing to left ventricular filling, experiments were performed in anesthetized, open-chest dogs with intact or mechanically constricted mitral ostium. Stroke volume was raised either by increasing left ventricular end-diastolic volume (preload) by blood volume expansion or by infusing isoproterenol, a beta-adrenergic agonist. In all experimental settings, stroke volume rose in proportion (r greater than 0.9) to the pressure time product (PTP = integral of the diastolic atrio-ventricular (A-V) pressure difference). During saline infusion atrial distention and contraction increased atrial pressure more than ventricular pressure whereas diastolic filling time (DFT) was not lengthened. Peak mitral and peak aortic flow rose almost equally. During isoproterenol infusion at constant heart rate (atrial pacing), the increase in PTP was mainly caused by a longer DFT. When heart rate was allowed to rise, DFT was reduced and the A-V pressure difference increased because of a greater reduction in ventricular than in atrial pressure in early diastole. Thus, the A-V pressure difference is generated in different ways by raising preload and inotropy with and without changes in heart rate.