The pressor response of vasopressin (AVP) is mediated by a calcium-dependent mechanism (VI-receptor), whereas its antidiuretic effect depends on c-ANP (V2-receptor). DDAVP (1-desamino-8-D-arginine vasopressin) is a synthetic V2 analog of AVP. AVP and DDAVP also increase FVIII:C vWF:Ag and tissue-type plasminogen activator (t-PA) in plasma. The mechanism by which AVP and DDAVP elevate these factors is unclear. Patients with X-linked nephrogenic diabetes insipidus (NDI) are resistant to the V2-mediated antidiuretic action of AVP and DDAVP. We therefore have studied the effect of DDAVP (0.4 ug/kg iv infusion in 10 min) in 2 brothers with NDI, their mother and an unrelated patient.In control subjects (n=12) FVIII:C rose 122 (6) % ,mean (SEM), vWF:Ag 104 (4) % and t-PA 115 (7) % over basal levels. This rise was associated with a fall in diascolic blood pressure -11 (3) mmHg and an increase in heart rate from 62 (4) to 91 (5) bpm. Plasma noradrenaline rose from 262 (34) to 590 (84) pg/ml and renin from 16 (3) to 42 (6) uU/ml. Ten out of 12 controls showed facial flusning. The patients with NDI had normal basal FVIII:C, vWF:Ag and t-PA levels. Plasma noradrenaline and renin were within the nor mam range. Tne patients with NDI were also resistant to the stimulatory effect of DDAVP on the release of FVIII:C, vWF:Ag and t-PA. They also showed no change in blood pressure, nearc rate, plasma noradrenaline and renin and had no facial flushing. The carrier had normal responses to DDAVP.Tne increase in FVII:C, vWF:Ag and t-PA and the hemodynamic responses after DDAVP infusion probably appear to depend on extrarenal V2-receptor activation. DDAVP cannot be used in identifying carriers in families at risk.