Water drinking elicits a profound sympathetically mediated pressor response in patients with autonomic failure. To further elucidate the mechanism of the response, we assessed the acute effect of drinking water on supine blood pressure and heart rate in 13 tetraplegic patients (12 men, 1 woman; 39+/-4 years of age; body mass index, 25+/-1 kg/m2) with complete spinal cord injury (C2 to C7). Heart rate and finger blood pressure were recorded continuously. Brachial blood pressure was measured every 5 minutes. Baroreflex sensitivity was assessed by the sequence method. Stroke volume was calculated by use of transthoracic bioimpedance. Patients were placed in the supine position with the upper body elevated by 15 degrees. After 30 minutes, supine patients ingested 500 mL of water and the following 60 minutes were monitored. Finger blood pressure at baseline was 123+/-8/65+/-4 mm Hg. Water drinking elicited a pressor response that was apparent within 5 minutes and reached a maximum of 138+/-8/73+/-4 mm Hg after 35 to 40 minutes (P<0.05). Heart rate decreased from 64+/-2 bpm at baseline to 60+/-2 bpm (P<0.001). The mean area under the curve for brachial systolic blood pressure changes differed significantly from zero (364+/-151 mm Hg/min). Total peripheral resistance increased by 15+/-4% (P<0.05). Baroreflex sensitivity increased from 18+/-5 ms/mm Hg at baseline to 23+/-6 ms/mm Hg at 35 minutes after water drinking (P<0.01). Water drinking elicits a pressor response even if the direct connection between brain stem cardiovascular centers and spinal sympathetic neurons is interrupted. This observation might suggest that water drinking activates postganglionic sympathetic neurons either directly or through a spinal reflex mechanism.