Temporal adjustment of the juxtaglomerular apparatus during sustained inhibition of proximal reabsorption

Tubuloglomerular feedback (TGF) stabilizes nephron function by causing chan ges in single-nephron GFR (SNGFR) to compensate for changes in late proxima l flow (VLP). TGF responds within seconds and reacts over a narrow range of VLP that surrounds normal VLP. To accommodate sustained increases in VLP, TGF must reset around the new flow. We studied TGF resetting by inhibiting proximal reabsorption with benzolamide (BNZ; administered repeatedly over a 24-hour period) in Wistar-Froemter rats. BNZ acutely activates TGF, thereb y reducing SNGFR. Micropuncture was performed 6-10 hours after the fourth B NZ dose, when diuresis had subsided. BNZ caused glomerular hyperfiltration, which was prevented with inhibitors of macula densa nitric oxide synthase (NOS). Because of hyperfiltration, BNZ increased VLP and distal flow but di d not affect the basal TGF stimulus (early distal salt concentration). BNZ slightly blunted normalized maximum TGF response and the basal state of TGF activation. BNZ sensitized SNGFR to reduction by S-methyl-thiocitrulline ( SMTC) and caused the maximum TGF response to be strengthened by SMTC. Sensi tization to type I NOS (NOS-I) blockers correlated with increased macula de nsa NOS-I immunoreactivity. Tubular transport measurements confirmed that B NZ affected TGF within the juxtaglomerular apparatus. During reduced proxim al reabsorption, TGF resets to accommodate increased flow and SNGFR through a mechanism involving macula densa NOS.