The study of salt-sensitive hypertension has been facilitated by development of genetic models, especially the Dahl/Rapp salt-sensitive (S) rat. S rats rapidly become hypertensive after initiation of a diet containing 8.0% NaCl and subsequently develop arteriolonephrosclerosis and renal failure, whereas the salt-resistant (R) strain remains normotensive on the same diet. The purpose of the present study was to use these strains to demonstrate the interactions between transforming growth factor-β1 (TGF-β1) and nitric oxide (NO). Young, male S and R rats were fed for 4 days diets that contained either 0.3 or 8.0% NaCl. An increase in dietary salt increased kinase activities of both p38 MAPK and p42/44 MAPK in cytoplasmic extracts from aortic rings and isolated glomeruli from both strains. Inhibition of either pathway with PD-098059 or SB-203580 decreased production of TGF-β1 and nitrate plus nitrite (NOx). In both strains, production of active TGF-β1 and NOx linearly correlated. Incubation of aortic rings and isolated glomeruli with the NO donor NOR3 decreased TGF-β1 levels, whereas the NO synthase inhibitor Nω-nitro-L-arginine methyl ester increased production. The inhibitory effect of NO on production of TGF-β1 was reduced in preparations from S rats. Although a close interrelationship existed between TGF-β1 and NO in both strains, production of TGF-β1 was increased in prehypertensive S rats and was further exaggerated with the increase in dietary salt intake. Augmented vascular and glomerular production of TGF-β1 and diminished NO may contribute to the development of hypertensive nephrosclerosis in S rats.