Water retention after oral chlorpropamide is associated with an increase in renal papillary arginine vasopressin receptors

Abstract

Hensen J, Haenelt M, Gross P. Water retention after oral chlorpropamide is associated with an increase in renal papillary arginine vasopressin receptors. Eur J Endocrinol 1995;132:459–64. ISSN 0804–4643 Chlorpropamide (CP), a sulfonylurea used for treatment of non-insulin dependent diabetes mellitus, is known to potentiate the antidiuretic action of arginine vasopressin (AVP), predisposing to hyponatremia. It has been suggested that CP acts directly on the antidiuretic vasopressin receptor. Detailed studies on the influence of CP on the AVP receptor, however, have been hampered by lack of a suitable radioligand. Using a newly developed radioiodinated derivative of AVP with high specific activity and high affinity for the AVP V2-receptor (125I-[8-(p-(OH)-phenylpropionyl)]-LVP), we studied the role of AVP V2-receptors in CP-induced water retention. Male-Sprague-Dawley rats were treated orally with 40 mg CP/day or placebo for 7 days, after which Scatchard analysis was performed using membranes prepared from homogenized renal papilla. After oral water load, CP-treated rats but not control rats showed a significant decrease in plasma osmolality (289 ±2.2 to 284±0.8 mosmol/kg, p < 0.05). The Kd was 0.69 ± 0.16 nmol/l in controls and 0.70 ± 0.12 nmol/l after CP treatment (NS); Bmax was 129 ± 5.3 nmol/kg protein in controls (N = 8). Chlorpropamide significantly increased receptor density (Bmax) to 167±8.4 nmol/kg protein (N = 8) (p<0.05). Plasma AVP did not change significantly during CP treatment. These data show for the first time that CP in vivo increases the density of AVP V2 receptors without altering plasma AVP. This is associated with an impairment in water excretion. Our experiments and recent reports on CP-induced inhibition of AVP binding suggest that the AVP augmentation effect of CP is related to interference of CP with the AVP V2-receptor. Johannes Hensen, Department of Medicine I, Division of Endocrinology and Metabolism, Krankenhausstr. 12, 91054 Erlangen, Germany