Sixteen sheep were surgically prepared for chronic study. Seven days later, Escherichia coli endotoxin (10 ng/kg/min, lipopolysaccharide (LPS) group, n = 10) or an equivalent amount of 0.9% NaCl (Control group n = 6) was administered. Between 1 and 8 h post-LPS, there was a hypodynamic state with low cardiac index (Cl, LPS 5.0 ± 0.2; sham 6.3 ± 0.4 liters/min/m2 at 4 h). During this period, the left ventricular end-systolic pressure-diameter relationship (ESPDR), a sensitive index of myocardial contractility, was also lower (LPS 10.4 ± 1.2; sham 17.2 ± 0.8 mmHg/mm). Mean pulmonary arterial pressure (PAP) and pulmonary vascular resistance index (PVRI) were remarkably increased 1 h after the administration of LPS (PAP: LPS 37.5 ± 1.9; sham 21.8 ± 0.9 mmHg, PVRI: LPS 600 ± 58; sham 158 ± 23 dynes · s · cm-5 · m2). The early changes in cardiopulmonary function occurred concomitantly with an elevation in tumor necrosis factor (LPS 1221 ± 520; sham 0 ± 0 pg/ml) and thromboxane B2 (LPS 1382 ± 266; baseline 82 ± 20 pg/ml) in arterial blood. Following this first phase, the sheep presented a persistent hyperdynamic state characterized by a significant increase in Cl. The ESPDR continued to fall. By 24 h post-LPS the Cl was 10.1 ± 0.5 liters/min/m2 (sham, 6.3 ± 0.3) but the ESPDR had fallen to 8.2 ± 2.3 mmHg/mm (sham 16.0 ± 3.0). The pulmonary hypertension was maintained for the duration of the LPS infusion. On the other hand, the pulmonary vascular resistance had returned to near the baseline value by 16 h after the endotoxin infusion. PaO2 fell and pulmonary shunt fraction rose in the LPS group at 24 h (PaO2: LPS 85 ± 9; sham 115 ± 4 mmHg, shunt: LPS 0.28 ± 0.04; sham 0.09 ± 0.01). Lung lymph flow (LPS 39.1 ± 6.5; sham 8.1 ± 0.8 ml/h) and wet: dry ratio (LPS 5.54 ± 0.13; sham 4.89 ± 0.09) were increased in LPS group at 24 h post-LPS. In our model of hyperdynamic state of sepsis simulating the human condition there is an increased Cl despite a significant depression in myocardial contractility and acute lung injury.