A possible gender difference in the antidiuretic activity of vasopressin was studied in male and female Sprague-Dawley rats. Infusion of vasopressin (3-100 pg.kg-1.min) into conscious, chronically instrumented water-loaded rats resulted in a dose-dependent antidiuresis in both male and female rats. Male rats, however, were more than three times more sensitive to vasopressin than female rats. Thus the effective doses of vasopressin (pg.kg-1.min-1) to decrease urine flow to 30 microliters.min-1.100 g-1 (18 +/- 5 in males; 58 +/- 12 in females), to increase urine osmolality to 600 mosmol/kgH2O (35 +/- 5 in males; 119 +/- 15 in females), and to decrease free water clearance to 30 microliters.min-1.100 g-1 (8 +/- 3 in males; 28 +/- 7 in females) were significantly (P < 0.05) lower in males. Furthermore, in vitro studies in papillary collecting duct cells demonstrated a significantly higher density of vasopressin V2 receptors and a greater ability of vasopressin to stimulate adenosine 3',5'-cyclic monophosphate (cAMP) accumulation in males than in females. Vasopressin V2-receptor density (maximum binding) was 359 +/- 47 and 238 +/- 22 fmol/mg in male and female rats, respectively (P < 0.05). There was no difference in apparent dissociation constants (Kd). Vasopressin resulted in a dose-dependent increase in cAMP accumulation in papillary collecting duct cells, and at the highest concentration of vasopressin used (10(-8) M) cAMP increased from 44 +/- 10 to 182 +/- 51 fmol/micrograms protein in males and from 30 +/- 4 to 91 +/- 18 fmol/micrograms protein in females (P < 0.05). (ABSTRACT TRUNCATED AT 250 WORDS)