Nephron site of effect of nonsteroidal anti-inflammatory drugs on solute excretion in humans

Abstract

Indomethacin and other nonsteroidal anti-inflammatory drugs (NSAIDs) decrease solute excretion when administered acutely to normal subjects. We performed clearance studies during water loading of 10 normal volunteers and during hydropenia in eight additional subjects to determine the nephron site of this effect using indomethacin and carprofen as inhibitors of prostaglandin (PG) synthesis. Their administration decreased fractional excretion of sodium, chloride, and volume. During water loading, fractional clearance of free water decreased from 0.13 +/- 0.04 during the control study to 0.09 +/- 0.03 and 0.06 +/- 0.02 with indomethacin and carprofen, respectively. However, fractional delivery of solute to the dilution segment decreased in parallel such that free water clearance corrected for delivery did not change with either drug. In humans, therefore, the decrement in solute excretion that occurs with administration of NSAIDs occurs prior to the diluting segment. During hydropenia, free water reabsorption relative to osmolar clearance increased (P less than 0.01). In both studies, neither the marker of renal perfusion or of proximal nephron function changed with inhibition of PG synthesis. The data indicate that at the tubular level, NSAIDs increase solute reabsorption at the medullary segment of the thick ascending limb of the loop of Henle. Therefore, a physiologic role of renal prostaglandins at this nephron site is implied.

Enalapril attenuates natriuresis of atrial natriuretic factor in humans.

“…22 The rise in free water clearance suggests increased solute delivery to the diluting segment, defined as the nephron beyond the point of isotonicity in the thick ascending limb of Henle's loop. 18 C H2O / (C H20 + C a ) , an index of diluting segment reabsorption, was decreased. The excretion of phosphate, uric acid, and lithium, which are mainly reabsorbed in the proximal tubules, 2021 and of magnesium, which is mainly reabsorbed in the thick ascending limb of Henle's loop, 23 was increased.…”

“…Free water clearance (Cuv)) during maximal water diuresis was taken as an index of sodium reabsorption in the diluting segment, which is defined as the nephron beyond the point of isotonicity in the thick ascending limb of Henle's loop. 18 Free water clearance plus the clearance of chloride (C a ) was regarded as an index of solute delivery to the diluting segment. The equation (C-H20 + C a )/C ta therefore represents an approximation of fractional solute delivery to the diluting segment, and the equation C H2C /(C H2O + C a ) is an approximation of diluting segment reabsorption.…”

Renal Function in a Rat Model of Analgesic Nephropathy: Effect of Chloroquine

“…Paracetamol inhibits PGE 2 synthesis, which is the primary prostaglandin affecting medullary hemodynamics and sodium and water handling (Dunn, 1998). Prostaglandins increase renal blood flow, reducing proximal reabsorption of sodium (Ichikawa and Brenner, 1980), while directly inhibiting sodium reabsorption by the thick ascending limb (Kaojarern et al, 1983). Thus, inhibition of PGE 2 synthesis is likely to cause a reduction in sodium excretion, as was observed in paracetamol-treated rats.…”

Opposite effects of enalapril and nitrendipine on natriuretic response to atrial natriuretic factor. Renal function evaluated with clearance studies in humans.

“…Free water clearance (C HO ) during maximal diuresis was taken as an index of sodium reabsorption in the diluting segment, which is defined as the nephron beyond the point of isotonicity in the thick ascending limb of Henle's loop. 10 The C H2 o plus the clearance of chloride (CQ) was regarded as an index of delivery to the diluting segment. Changes in the term [(C H2 o+Cci)/Q nu iiJ therefore represent an index of changes in the fractional solute delivery to the diluting segment, and changes in the term [C HlO l …”