Studies on the tubulo-glomerular feedback system in the rat. The mechanism of reduction in filtration rate with benzolamide.

Abstract

The specific mechanism whereby superficial nephron glomerular filtration rate (sngfr) is reduced after the administration of benzolamide, a carbonic anhydrase inhibitor with a primary inhibitory effect in the proximal tubule, have been examined by measuring pertinent pressures, flows, and glomerular permeabilities in the hydropenic Munich-Wistar rat, a strain with surface glomeruli. Because benzolamide decreases absolute proximal reabsorptive rate, the rate of delivery of tubular fluid to the distal nephron should be at least transiently increased and may reduce sngfr by activating the tubulo-glomerular feedback system. Sngfr fell from 29.2+/2.0 to 2.1+/3.1 nl/min (P less than 0.01) after benzolamide (group 1), a percentage reduction equal to kidney glomerular filtration rate and similar to sngfr obtained in collections from distal tubules. Separate studies (group 2) revealed that if transient increases in distal nephron delivery were prevented by insertion of a long oil block in proximal tubules before control, the decrease in sngfr was prevented (30.3+/1.0 vs. 30.3+/1.8 nl/min, P greater than 0.9). In paired "unblocked" nephrons in the same rats, sngfr fell in group 2 (33.0+/1.0 vs. 25.2+/2.3 nl/min, P less than 0.01). In "blocked" nephrons in which sngfr reduction was prevented, the rate of fluid leaving the proximal tubule increased from 16.9+/ to 23.1+/1.0 nl/min (P less than 0.01). In group 1 studies in which sngfr fell and transient increases in flow out of the last segment of the proximal tubule (distal delivery) (approximately equal to 8 nl/min) were not prevented, steady-state distal delivery was unchanged by benzolamide (13.9+/1.1 vs. 14.2+/2.2 nl/min). Also, sngfr returned toward control, pre-benzolamide values, when a proximal oil block was placed for 15 min and the rate of distal delivery reduced after benzolamide administration, which suggests that this activation was reversible. These data suggest that activation of tubulo-glomerular feedback by transient increases in distal delivery was responsible for decreases in sngfr. Analysis of all determinants of glomerular ultra-filtration revealed that the efferent mechanism leading to reduced sngfr after benzolamide was decreased nephron plasma flow (101+/13 vs. 66+/13 nl/min, P less than 0.01). Hydrostatic pressure and the glomerular permeability coefficient did not contribute to reductions in sngfr with benzolamide. Because the rate of distal delivery remained constant in spite of large changes in both sngfr and absolute proximal reabsorptive rate, it is suggested that the rate of distal delivery may be the physiologic entity that is regulated by the tubulo-glomerular feedback system via alterations in sngfr.

The macula densa is worth its salt

“…These authors have shown earlier that an acute inhibition of proximal NaHCO 3 absorption by the carbonic anhydrase inhibitor benzolamide causes an increase in salt delivery to the macula densa, accompanied by the predicted TGF-mediated reduction in filtration rate (16). Their new results demonstrate that repeated administration of benzolamide over 24 hours, which results in prolonged hyperperfusion of the macula densa, induces a rightward and upward shift of the TGF curve ( Figure 2).…”

Effects of acetazolamide on kidney function in Type 1 (insulin-dependent) diabetic patients with diabetic nephropathy

“…Experimental studies in animals have shown that carbonic anhydrase inhibitors reduce proximal tubular reabsorption of water and sodium [4,5,[20][21][22]. Acute administration of acetazolamide has been reported to increase lithium clearance and reduce proximal tubular reabsorption of sodium and water in man [16].…”

“…Acute administration of acetazolamide has been reported to increase lithium clearance and reduce proximal tubular reabsorption of sodium and water in man [16]. The acute decline in GFR is probably mediated by the tubulo-glomerular feedback mechanism [4,5,20,22].…”

“…Intravenous injection of acetazolamide induces a slight (10-20%) decline in GFR in normal man [2,3]. Micropuncture studies in rats have shown reduced proximal tubular reabsorption of fluid and electrolytes, suggesting activation of the tubuloglomerular feedback mechanism as the main cause of the reduced GFR during intravenous administration of acetazolamide [4,5].…”

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

“…BNZ acutely reduces proximal reabsorption by approximately 50%, thereby increasing fluid entry to the loop of Henle, with subsequent activation of TGF. Administered acutely, BNZ causes a TGF-mediated reduction in GFR (3). (In pilot studies performed in awake rats, single intraperitoneal doses of BNZ exerted a diuretic effect that lasted less than 6 hours.).…”