The mechanism by which clonidine suppresses renin secretion was investigated in pentobarbital-anesthetized dogs in which renal perfusion pressure was controlled by means of an aortic clamp. Clonidine (30 microgram/kg, iv) lowered mean arterial pressure (MAP) from 124 +/- 8 to 104 +/- 4 mm Hg (P less than 0.01) and reduced plasma renin activity (PRA) to 32 +/- 4 percent of the control value (P less than 0.01) after 60 minutes. Ganglion blockade with pentolinium (3 mg/kg, im) decreased MAP from 148+/- 7 to 117 +/- 3 mm Hg (P less than 0.01) and reduced PRA to 55 +/- 13 percent of the control value (P less than 0.05) after 45 minutes. Pentolinium converted the hypotension produced by clonidine to hypertension (108 +/- 9 to 146 +/- 10 mm Hg at 60 minutes, P less than 0.05) and abolished the suppression of PRA (105 +/- 14 percent of control at 60 minutes, P less than 0.05). In a further series of experiments, the effects of oxymetazoline, an alpha-adrenergic receptor agonist which is closely related to clonidine but which does not cross the blood brain barrier, were studied. Oxymetazoline (10 microgram/kg, iv) increased MAP from 127 +/- 3 to 154 +/- 2 mm Hg (P less than 0.01) and elevated PRA TO 176 +/- 22 percent of the control value (P less than 0.02) after 30 minutes. A higher dose of oxymetazoline (30 microgram/kg) increased MAP from 129 +/- 10 to 161 +/- 9 mm Hg (P less than 0.05) and increased PRA to 256+/- 37 percent of control (P less than 0.05) after 30 minutes. Taken together, these data support the hypothesis that the inhibition of renin secretion by clonidine results from a centrally mediated decrease in sympathetic neural activity.