Evidence has been provided that the immunological mechanism is involved in the genesis or maintenance of hypertension. In the present study, we investigated the effects of interferon gamma, a potent immunomodulator derived from lymphocytes, on hypertension and organ damage in Dahl salt-sensitive rats and in spontaneously hypertensive rats. Subcutaneous injection of interferon gamma (5 x 10(4) units/kg body wt once a week for 10 weeks) reduced blood pressure in Dahl salt-sensitive rats fed a 4% high salt diet (174 versus 194 mm Hg, p less than 0.025). This blood pressure reduction was associated with an improvement of renal functions, an increase in glomerular filtration rate (690 versus 569 ml/day/100 g body wt, p less than 0.05), and decreases in urinary protein excretion (48 versus 78 mg/day/100 g body wt, p less than 0.025) and urinary N-acetyl-beta-D-glucosaminidase excretion (143 versus 183 milliunits/day/100 g body wt, p less than 0.05). Morphological investigation showed a marked resolution of the vascular injuries seen in untreated Dahl salt-sensitive rats, e.g., intimal and medial hyperplasia, with infiltration of inflammatory cells, and significant amelioration of the glomerular sclerotic changes. In contrast, interferon gamma affected neither blood pressure nor renal functions in spontaneously hypertensive rats. These data indicate that interferon gamma ameliorates the development of hypertension and vascular and renal injuries in Dahl salt-sensitive rats. The resolution of vascular and renal injuries contributes, in part, to the antihypertensive action of interferon gamma.