Intravenous desmopressin, a synthetic antidiuretic hormone, resulted in a dose-dependent increase in intraocular pressure (IOP) in rabbits. IOP was increased 3.6 +/- 0.8 mm Hg 6 hr following injection of desmopressin 200 mUnits/kg with the increase lasting over 10 hr. IOP returned to baseline 24 hr after the injection. Systemic blood pressure, plasma osmolarity and arterial blood gases were not altered by desmopressin. The increased IOP was not associated with alterations in measured outflow facility or episcleral venous pressure. Five hours after desmopressin injection, calculated aqueous humor flow was increased approximately 57%. Aqueous humor ascorbate measurements for calculation of flow to diffusion ratios and anterior chamber fluorophotometry also were consistent with an increased rate of aqueous humor formation as the mechanism for the IOP elevation. Desmopressin administration did not increase aqueous humor protein or aqueous humor cyclic AMP concentration. Systemic pretreatment with indomethacin only partially blocked the IOP increase. Systemic pretreatment with demeclocycline completely blocked the desmopressin-induced increase in IOP.