Normal Fibrinolytic Responses to 1 -Desamino-8-O-Arginine Vasopressin in Patients with Nephrogenic Diabetes insipidus Caused by Mutations in the Aquaporin 2 Gene

Three patients with autosomal-recessive nephrogenic diabetes insipidus (NDI), homozygous for mutations in the aquaporin 2 gene (AQP2), were tested for their fibrinolytic and hemodynamic responses to intravenous adm inistration of l-desamino-8-D-arginine vasopressin (DDAVP). They all showed an increase of tissue-type plasminogen activator antigen, facial flush­ ing, an increase of heart rate and a decrease of diastolic blood pressure. These results confirm the hypothesis that NDI patients with an AQP2 delect can be discrim inated from NDI patients with a vasopressin type 2 receptor defect by their normal extrarenal responses to DDAVP. Introduction polydipsia and an increased risk of dehydration. Further­ more, most NDI patients lack the extrarenal responses to The m ain functions of the neurohypophyseal horm one DDAVP, indicating a generalized V2 receptor defect [3, arginine vasopressin (AVP) are reflected by its two names; 7-9]. Evidence for the hypothesis that a V2 receptor ‘vasopressin’ refers to the vasoconstriction resulting from defect causes NDI was gained when m utations in the V2 binding to vasopressin type 1 receptors on vascular receptor gene were found in patients with the X-linked smooth muscle cells, while ‘antidiuretic horm one’ desigrecessive form of the disease [ 10]. Some patients have nates the urinary concentration occurring in response to been reported, however, who showed normal fibrinolytic, binding to vasopressin type 2 (V2) receptors in the renal coagulation and hemodynamic responses to DDAVP, in­ collecting ducts. Strong activation of the V2 receptor can dicating that their extrarenal V2 receptor functions norbe accomplished by adm in istra tion of l-desam ino-8-.Dmally [11-13]. The observation that, in these patients, arginine vasopressin (DDAVP), a V2 receptor agonist only the renal response to DDAVP is impaired, can be with an an tid iuretic /pressor ratio o f 4,000 [ 1 ]. In addition explained by the presence of a defect in the antidiuretic to its renal antid iuretic action, D D A V P elicits vasodila­ tion and an increase o f coagulation and fibrinolysis facAVP pathway beyond the V2 receptor. Recently, the gene was cloned which encodes the aquaporin 2 (AQP2) water tors [2, 3]. T he exact location o f the V2 receptors which channel, a protein that is inserted into the apical memm ediate these effects is unknow n. Studies in anephric brane of collecting duct cells in response to activation of subjects have excluded the possibility that they are situthe V2 receptor [14]. The first patient in which we ated in the kidney [2, 4], M oreover, evidence supporting observed a normal extrarenal response to DDAVP was the presence o f V2 receptors on monocytes has been demonstrated to be a compound heterozygote for mutagained [5, 6], H ereditary nephrogenic diabetes insipidus tions in this autosomal AQP2 gene, a finding which con(NDI) is a rare disease in which the antidiuretic response firmed the postulated presence of a renal post-V2-recepto AVP and D D A V P is lacking, resulting in polyuria, tor defect [15]. Since this is the onlv patient with a proven