Previous studies have shown that hypotension produced by drugs facilitating gamma-aminobutyric acid (GABA) transmission was caused by a decrease in sympathetic nervous system outflow. We attempted to determine if GABA agonists and GABA uptake inhibitors could also lower arterial pressure that was elevated by increasing the secretion of endogenous vasopressin. GABA and nipecotic acid, an uptake inhibitor of GABA, were administered intraventricularly to determine the cardiovascular effects of these agents in nephrectomized rats made acutely hypertensive with hypertonic saline. A 2-hr i.v. infusion of hypertonic saline (3.0 mEq/ml) increased arterial pressure from 119 +/- 2 to 157 +/- 2 mm Hg. Intraventricular administration of artificial cerebrospinal fluid, 100 micrograms of GABA and 175 micrograms of nipecotic acid produced a peak decrease in blood pressure of 0 +/- 0, 30 +/- 4 and 22 +/- 3 mm Hg, respectively. In nephrectomized rats receiving an equal volume of isotonic saline (0.15 mEq/ml), infused i.v. arterial pressure did not change. In these animals, central infusions of artificial cerebrospinal fluid, 100 micrograms of GABA and 175 micrograms of nipecotic acid decreased blood pressure only 1 +/- 1, 13 +/- 2 and 8 +/- 3 mm Hg, respectively. Further experiments utilizing nephrectomized rats infused with hypertonic saline were designed to determine the mechanism for the augmented depressor response produced by these agents. Elimination of the contribution of vasopressin to arterial pressure with a vascular vasopressin antagonist reduced the depressor responses produced by 100 micrograms of GABA and 175 micrograms of nipecotic acid to 10 +/- 3 and 8 +/- 3 mm Hg, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)