Heart-lung transplantation results in afferent and efferent denervation of the transplanted organs including interruption of the central connections from the low-pressure receptors in the atria and pulmonary veins. We investigated whether the cardiovascular and neurohumoral responses to the postural stimulus of head-up tilt were affected after transplantation. Responses in eight heart-lung transplant recipients were studied and compared with those in eight normal subjects matched for age and sex during passive head-up tilt at 45° for 1 hour. The transplant group had a higher initial heart rate (99±2 versus 68±2 beats/min, p<0.001) and diastolic blood pressure (88±5 versus 76±2 mm Hg, p<0.05) than did the control group. The increases in heart rate and diastolic blood pressure during head-up tilt were similar in the two groups. Systolic blood pressure remained unchanged. The decrease in cardiac output (30% versus 18%, p<0.05) and the increase in systemic vascular resistance (52% versus 28%, p<0.05) were greater in the transplant group. Baseline levels of norepinephrine, epinephrine, vasopressin, and plasma renin activity were similar in the two groups. Atrial natriuretic peptide concentrations were higher in the transplant group (26±3.8 versus 9.7±1.6 pmol/1, p<0.001). During head-up tilt, plasma norepinephrine levels increased to a greater extent in the transplant group than in the control group (83% versus 53%, p<0.01), indicating an increased sympathetic response. In contrast, plasma renin activity increased significantly in the control group but not in the transplant group. Plasma vasopressin concentrations remained unchanged, whereas atrial natriuretic peptide concentrations decreased significantly in both groups. The pattern of cardiovascular and neuroendocrine responses to head-up tilt was altered in heart-lung transplant recipients, who had a greater dependence on sympathetic-mediated vasoconstriction, although their ability to maintain systemic blood pressure during this postural stress was unaffected.