We examined the role of nitric oxide (NO) in the inherited resistance or susceptibility to hypertension in the Sabra hypertension-prone (SBH) and hypertension-resistant (SBN) rat. Basal mean arterial blood pressure was significantly greater in SBH than in SBN rats. Phenylephrine elevated blood pressure to a similar extent in both substrains, whereas the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) had a greater pressor effect in SBN rats. The vasoconstrictor potency of phenylephrine was significantly higher in endothelium-intact aortic rings from the SBH rat, whereas the vasoconstrictor potency of L-NMMA was higher in those from the SBN substrain. Acetylcholine-induced endothelium-dependent relaxation was greater in aortic rings from SBN rats. The vasodilator potency of glyceryl trinitrate was significantly higher in aortic rings from SBH rats and was enhanced after endothelium removal. Both the activity of calcium-dependent NO synthase from aortic endothelial cells and the basal concentration of nitrite/nitrate in plasma were significantly greater in SBN than in SBH rats. In normotensive Wistar rats, basal mean arterial blood pressure, the pressor effect of L-NMMA, endothelial NO synthase activity, and plasma nitrite/ nitrate concentrations were all between the values in SBH and SBN rats. These results indicate that a decrease in NO generation plays a role in the susceptibility of SBH rats to hypertension. Furthermore, the resistance to hypertension in the SBN strain may be related to increased NO generation.