Effects of somatostatin (SRIF) on vasopressin-stimulated antidiuresis and on cyclic AMP in renal medulla in vivo and in microdissected tubule segments were examined in rats. An intravenous infusion of SRIF abolished vasopressin-induced antidiuresis without significant changes in urinary solutes and creatinine excretion in water diuresing rats: urinary osmolality rose from 131 +/- 12 to 587 +/- 20 mOsm/kg H2O in rats receiving vasopressin while urinary osmolality rose from 103 +/- 7 to only 258 +/- 25 mOsm/kg H2O in response to vasopressin with SRIF. This effect of SRIF was reversible. SRIF diminished only slightly the vasopressin-stimulated increases in cyclic AMP in renal medulla in vivo. In both cortical and medullary collecting tubules as well as in the medullary thick ascending limb of Henle's loop microdissected from rat kidney, SRIF partially inhibited vasopressin-dependent increases in cell cyclic AMP concentrations. These data demonstrate an inhibition by SRIF of vasopressin-stimulated anti-diuresis in rats and suggest that the mechanisms involved may be, at least partly, an inhibition of cyclic AMP formation in response to vasopressin in the collecting tubules.