In order to investigate the mechanisms of the hyperreactivity of the tubuloglomerular feedback (TGF) mechanism in spontaneous hypertensive rats (SHR) the resetting of TGF by chronic dietary NaCl loading was studied in SHR and normotensive Wistar Kyoto rats (WKY). This treatment is known to reset the TGF by an inhibitory factor in tubular fluid and not by alterations of the intrinsic characteristics of the juxtaglomerular apparatus (JGA). TGF reactivity, and its resetting, were determined by loop of Henle perfusion with artificial late proximal tubular fluid and with harvested endogenous tubular fluid respectively. Dietary effects of the high sodium intake were measured by means of the systolic blood pressure (SBP), plasma volume (PV), and renal sodium excretion. The 4-week dietary treatment had no significant influence on SBP in WKY, whereas it accelerated the rise of SBP in SHR significantly. After 1 week of treatment, PV was increased in both WKY and SHR as compared with the control groups kept on the normal diet. Whereas PV in WKY declined to control values over the next 3 weeks, SHR remained expanded, GFR was similar in all groups, whereas urinary sodium excretion was significantly increased in salt-loaded SHR and WKY. Dietary salt loading was paralleled by the appearance of a TGF-inhibiting substance in the tubular fluid in SHR and WKY. However, when assayed with artificial late proximal tubular fluid, hyperreactivity was similar in normal and salt-loaded SHR as compared with WKY. Thus, in SHR TGF hyperreactivity is maintained in spite of volume expansion and TGF resetting by a humoral factor in tubular fluid. Under these circumstances, TGF hyperreactivity presumably results from intrinsic differences between SHR and WKY rats rather than from an activation of TGF by extracellular volume contraction.