WATER-RETENTION AFTER ORAL CHLORPROPAMIDE IS ASSOCIATED WITH AN INCREASE IN RENAL PAPILLARY ARGININE-VASOPRESSIN RECEPTORS

Chlorpropamide (CP), a sulfonylurea used for treatment of non-insulin dependent diabetes mellitus, is known to potentiate the antidiuretic a ction of arginine vasopressin (AVP), predisposing to hyponatremia. It has been suggested that CP acts directly on the antidiuretic vasopress in receptor. Detailed studies on the influence of CP on the AVP recept or, however, have been hampered by lack of a suitable radioligand. Usi ng a newly developed radioiodinated derivative of AVP with high specif ic activity and high affinity for the AVP V-2-receptor (I-125-[8-(p-(O H)-phenylpropionyl)]-LVP) we studied the role of AVP V-2-receptors in CP-induced water retention. Male-Sprague-Dawley rats were treated oral ly with 40 mg CP/day or placebo for 7 days, after which Scatchard anal ysis was performed using membranes prepared from homogenized renal pap illa. After oral water load, CP-treated rats but not control rats show ed a significant decrease in plasma osmolality (289 +/- 2.2 to 284 +/- 0.8 mosmol/kg, p < 0.05). The K-d was 0.69 +/- 0.16 nmol/l in control s and 0.70 +/- 0.1.2 nmol/l after CP treatment (NS); B-max was 129 +/- 5.3 nmol/kg protein in controls (N = 8). Chlorpropamide significantly increased receptor density (B-max) to 167 +/- 8.4 nmol/kg protein (N = 8) (p < 0.05). Plasma AVP did not change significantly during CP tre atment. These data show for the first time that CP in vivo increases t he density of AVP V-2 receptors without altering plasma AVP. This is a ssociated with an impairment in water excretion. Our experiments and r ecent reports on CP-induced inhibition of AVP binding suggest that the AVP augmentation effect of CP is related to interference of CP with t he AVP V-2-receptor.