This study of spontaneously hypertensive (SH) rats documents oral antihypertensive activity of the vasodilator Ofornine@, an anthranilamide whose effect was sustained, at least in part, by suppression of compensatory renal and neurohumoral responses. Doses of 2.5 to 100 mg/kg p.0. reduced systolic blood pressure (BP) by up to 75 mm Hg. Effect lasted 6-24 hr and did not diminish during a 16 day (25 mg/kg/day) regimen. Metoclopramide (1 0.0 mg/kg) and haloperidol (3.0 mg/kg) antagonized the antihypertensive effect. Antihypertensive activity was confirmed by direct (arterial cannula) monitoring where 0.001 -1 .O mg/kg i.v. reduced mean BP by 6-47% without tachycardia. Doses of 1-10 p,g/kg i.a. reduced perfusion pressure of the SH rat hindquarters by 35-74 mm Hg. A dose of 5.0 mg/kg p.0. reduced BP and urine norepinephrine levels of SH rats by 58 mm Hg and approximately 50% without raising plasma renin activity or causing sodium retention. However, Ofornine@ (25 mg/kg p.0. daily for 6 days) did not affect reflex bradycardic or tachycardic effects of phenylephrine and sodium nitroprusside in SH rats. These and other results indicate that Ofornine@ reduces SH rat blood pressure through vasodilating and presynaptic adrenolytic activities, and that a dopaminergic mechanism may be involved.