Figure 6.

Graphic representation of the hypothesis to account for the observed effects of BNZ on ambient SNGFR and VLP, and to justify performing measurements after BNZ rather than during BNZ. The sigmoid curves refer to various TGF curves. Solid lines refer to the dependence of VLP on SNGFR owing to proximal GTB. Points A–E refer to the operating points where the various TGF and GTB curves intersect. Arrows refer to the PDD at each operating point. The control nephron operates at point A. The immediate effect of BNZ is to reduce proximal reabsorption, thereby moving the nephron to point B, where the TGF curve is relatively flat. Under the continuous influence of BNZ, the TGF curve resets rightward and the nephron moves to point C, where TGF efficiency is restored. If, as we hypothesize, it is the persistent activation of TGF that provides the stimulus for TGF resetting, then it follows that SNGFR (C) ≤ SNGFR (A) and VLP (C) > VLP (A). However, establishing these 2 inequalities cannot verify TGF resetting, because the same inequalities apply to the relationship between point A and point B. Furthermore, administration of the diuretic BNZ might activate sodium-conserving mechanisms extrinsic to TGF, which would buffer the effect of BNZ on proximal reabsorption and exert a downward pressure on GFR through mechanisms that operate independently of TGF. Therefore, comparing point A with point C was not considered an appropriate means to test for TGF resetting during BNZ treatment. On the other hand, allowing proximal tubular reabsorption to increase by withdrawing BNZ would move the operating point to point D, where SNGFR (D) > SNGFR (A) and VLP (D) > VLP (A). These 2 inequalities cannot both be satisfied unless there is rightward and/or upward resetting of TGF. Furthermore, increases in SNGFR are contrary to any expected outcome mediated through the effects of BNZ on extracellular volume. Therefore, establishing that SNGFR (D) > SNGFR (A) and VLP (D) > VLP (A) is sufficient to validate that TGF has reset. However, it cannot be determined from the coordinates of the operating point whether the resetting is primarily rightward (point D) or rightward and upward (point E). This latter issue can be addressed by the testing for changes in the PDD and by measuring SNGFR from the proximal tubule during minimum and maximum stimulation of TGF. If TGF resets purely rightward during BNZ, then the increase in ambient SNGFR after BNZ is withdrawn will be associated with a subnormal PDD (point D). If the PDD is not subnormal after withdrawal of BNZ, then there must be an upward component to the resetting of TGF (point E). In the present experiments, the PDD was unaffected by previous treatment with BNZ, inferring that the TGF curve had shifted both upward and rightward.