Our previous studies demonstrated that NaCl-sensitive spontaneously hypertensive rats (SHR) of the Okamoto strain exhibit increased blood pressure and reduced noradrenergic input to the anterior hypothalamus area when fed high NaCl diets. The current study tested the hypotheses that 1) release of atrial natriuretic factor (ANF) into the plasma is Impaired in NaCI-loaded SHR, a defect that would tend to elevate blood pressure, and 2) ANF levels in regions of brain involved in blood pressure regulation, such as the anterior hypothalamk area, are altered in SHR. SHR and control Wistar-Kyoto rats (WKY) were placed on 1% or 8% NaCl diets at age 7 weeks; 2 weeks later, ANF levels were measured in plasma, left and right atria, anterior hypothalamic area, ventral hypothalamic area, posterior hypothalamic area, pons, and medulla by radioimmunoassay. Blood for ANF assay was obtained from intra-arterial cannulas in conscious, unrestrained rats studied in the resting state. The 8% NaCl diet produced an increase in blood pressure in the SHR, but not in the WKY. Plasma ANF levels were significantly greater in WKY fed 8% NaCl than in WKY fed 1% NaCl, but dietary NaCl loading did not produce similar increases in plasma ANF in the SHR. Plasma ANF levels were not significantly different between SHR and WKY fed the 1% NaCl diet. The observation that dietary NaCl loading stimulated ANF release into the plasma in WKY but not in SHR suggests that the exacerbation in hypertension seen in NaCI-loaded SHR may be related to an impairment in ANF release. In addition, ANF stores were elevated in the anterior hypothalamic area of SHR fed either diet as compared with WKY. The role of this alteration in central nervous system ANF in the pathogenesis of NaCl-sensitive hypertension remains to be determined. © Williams and Wilkins 1988. All Rights Reserved.